Substituted Pyrazolyl Urea Derivatives Useful in the Treatment of Cancer

ABSTRACT

The present invention relates to compounds of formula (I), pharmaceutical compositions which contain them and methods for treating cancer using compounds of formula (I).

FIELD OF THE INVENTION

This invention relates to novel compounds, pharmaceutical compositionscontaining such compounds and the use of those compounds or compositionsfor treating hyper-proliferative and angiogenesis disorders, as a soleagent or in combination with other active ingredients, e.g., cytotoxictherapies.

BACKGROUND OF THE INVENTION

To support progressive tumor growth beyond the size of 1-2 mm³, it isrecognized that tumor cells require a functional stroma, a supportstructure consisting of fibroblast, smooth muscle cells, endothelialcells, extracellular matrix proteins, and soluble factors (Folkman, J.,Semin Oncol, 2002. 29(6 Suppl 16), 15-8). Tumors induce the formation ofstromal tissues through the secretion of soluble growth factors such asPDGF and transforming growth factor-beta (TGF-beta), which in turnstimulate the secretion of complimentary factors by host cells such asfibroblast growth factor (FGF), epidermal growth factor (EGF), andvascular endothelial growth factor (VEGF). These stimulatory factorsinduce the formation of new blood vessels, or angiogenesis, which bringsoxygen and nutrients to the tumor and allows it to grow and provides aroute for metastasis. It is believed some therapies directed atinhibiting stroma formation will inhibit the growth of epithelial tumorsfrom a wide variety of histological types. (George, D. Semin Oncol,2001. 28(5 Suppl 17), 27-33; Shaheen, R. M., et al., Cancer Res, 2001.61(4), 1464-8; Shaheen, R. M., et al. Cancer Res, 1999. 59(21), 5412-6).However, because of the complex nature and the multiple growth factorsinvolved in angiogenesis process and tumor progression, an agenttargeting a single pathway may have limited efficacy. It is desirable toprovide treatment against a number of key signaling pathways utilized bytumors to induce angiogenesis in the host stroma. These include PDGF, apotent stimulator of stroma formation (Ostman, A. and C. H. Heldin, AdvCancer Res, 2001, 80, 1-38), FGF, a chemo-attractant and mitogen forfibroblasts and endothelial cells, and VEGF, a potent regulator ofvascularization.

PDGF is another key regulator of stromal formation which is secreted bymany tumors in a paracrine fashion and is believed to promote the growthof fibroblasts, smooth muscle and endothelial cells, promoting stromaformation and angiogenesis. PDGF was originally identified as the v-sisoncogene product of the simian sarcoma virus (Heldin, C. H., et al., JCell Sci Suppl, 1985, 3, 65-76). The growth factor is made up of twopeptide chains, referred to as A or B chains which share 60% homology intheir primary amino acid sequence. The chains are disulfide cross linkedto form the 30 kDa mature protein composed of either M, BB or AB homo-or heterodimmers. PDGF is found at high levels in platelets, and isexpressed by endothelial cells and vascular smooth muscle cells. Inaddition, the production of PDGF is up regulated under low oxygenconditions such as those found in poorly vascularized tumor tissue(Kourembanas, S., et al., Kidney Int, 1997, 51(2), 438-43). PDGF bindswith high affinity to the PDGF receptor, a 1106 amino acid 124 kDatransmembrane tyrosine kinase receptor (Heldin, C. H., A. Ostman, and L.Ronnstrand, Biochim Biophys Acta, 1998. 1378(1), 79-113). PDGFR is foundas homo- or heterodimer chains which have 30% homology overall in theiramino acid sequence and 64% homology between their kinase domains(Heldin, C. H., et al. Embo J, 1988, 7(5), 1387-93). PDGFR is a memberof a family of tyrosine kinase receptors with split kinase domains thatincludes VEGFR2 (KDR), VEGFR3 (Flt4), c-Kit, and FLT3. The PDGF receptoris expressed primarily on fibroblast, smooth muscle cells, and pericytesand to a lesser extent on neurons, kidney mesangial, Leydig, and Schwanncells of the central nervous system. Upon binding to the receptor, PDGFinduces receptor dimerization and undergoes auto- andtrans-phosphorylation of tyrosine residues which increase the receptors'kinase activity and promotes the recruitment of downstream effectorsthrough the activation of SH2 protein binding domains. A number ofsignaling molecules form complexes with activated PDGFR includingPI-3-kinase, phospholipase C-gamma, src and GAP (GTPase activatingprotein for p21-ras) (Soskic, V., et al. Biochemistry, 1999, 38(6),1757-64). Through the activation of PI-3-kinase, PDGF activates the Rhosignaling pathway inducing cell motility and migration, and through theactivation of GAP, induces mitogenesis through the activation of p21-rasand the MAPK signaling pathway.

In adults, it is believed the major function of PDGF is to facilitateand increase the rate of wound healing and to maintain blood vesselhomeostasis (Baker, E. A. and D. J. Leaper, Wound Repair Regen, 2000.8(5), 392-8; Yu, J., A. Moon, and H. R. Kim, Biochem Biophys Res Commun,2001. 282(3), 697-700). PDGF is found at high concentrations inplatelets and is a potent chemoattractant for fibroblast, smooth musclecells, neutrophils and macrophages. In addition to its role in woundhealing PDGF is known to help maintain vascular homeostasis. During thedevelopment of new blood vessels, PDGF recruits pericytes and smoothmuscle cells that are needed for the structural integrity of thevessels. PDGF is thought to play a similar role during tumorneovascularization. As part of its role in angiogenesis PDGF controlsinterstitial fluid pressure, regulating the permeability of vesselsthrough its regulation of the interaction between connective tissuecells and the extracellular matrix. Inhibiting PDGFR activity can lowerinterstitial pressure and facilitate the influx of cytotoxics intotumors improving the anti-tumor efficacy of these agents (Pietras, K.,et al. Cancer Res, 2002. 62(19), 5476-84; Pietras, K., et al. CancerRes, 2001. 61(7), 2929-34).

PDGF can promote tumor growth through either the paracrine or autocrinestimulation of PDGFR receptors on stromal cells or tumor cells directly,or through the amplification of the receptor or activation of thereceptor by recombination. Over expressed PDGF can transform humanmelanoma cells and keratinocytes (Forsberg, K., et al. Proc Natl AcadSci USA., 1993. 90(2), 393-7; Skobe, M. and N. E. Fusenig, Proc NatlAcad Sci USA, 1998. 95(3), 1050-5), two cell types that do not expressPDGF receptors, presumably by the direct effect of PDGF on stromaformation and induction of angiogenesis. This paracrine stimulation oftumor stroma is also observed in carcinomas of the colon, lung, breast,and prostate (Bhardwaj, B., et al. Clin Cancer Res, 1996, 2(4), 773-82;Nakanishi, K., et al. Mod Pathol, 1997, 10(4), 341-7; Sundberg, C., etal. Am J Pathol, 1997, 151(2), 479-92; Lindmark, G., et al. Lab Invest,1993, 69(6), 682-9; Vignaud, J. M., et al, Cancer Res, 1994, 54(20),5455-63) where the tumors express PDGF, but not the receptor. Theautocrine stimulation of tumor cell growth, where a large fraction oftumors analyzed express both the ligand PDGF and the receptor, has beenreported in glioblastomas (Fleming, T. P., et al. Cancer Res, 1992,52(16), 4550-3), soft tissue sarcomas (Wang, J., M. D. Coltrera, and A.M. Gown, Cancer Res, 1994, 54(2), 560-4) and cancers of the ovary(Henriksen, R., et al. Cancer Res, 1993, 53(19), 4550-4), prostate(Fudge, K., C. Y. Wang, and M. E. Stearns, Mod Pathol, 1994, 7(5),549-54), pancreas (Funa, K., et al. Cancer Res, 1990, 50(3), 748-53) andlung (Antoniades, H. N., et al., Proc Natl Acad Sci USA, 1992, 89(9),3942-6). Ligand independent activation of the receptor is found to alesser extent but has been reported in chronic myelomonocytic leukemia(CMML) where the a chromosomal translocation event forms a fusionprotein between the Ets-like transcription factor TEL and the PDGFreceptor. In addition, activating mutations in PDGFR have been found ingastrointestinal stromal tumors in which c-Kit activation is notinvolved (Heinrich, M. C., et al., Science, 2003, 9, 9).

Certain PDGFR inhibitors will interfere with tumor stromal developmentand are believed to inhibit tumor growth and metastasis.

Another major regulator of angiogenesis and vasculogenesis in bothembryonic development and some angiogenic-dependent diseases is vascularendothelial growth factor (VEGF; also called vascular permeabilityfactor, VPF). VEGF represents a family of isoforms of mitogens existingin homodimeric forms due to alternative RNA splicing. The VEGF isoformsare reported to be highly specific for vascular endothelial cells (forreviews, see: Farrara et al. Endocr. Rev. 1992, 13, 18; Neufield et al.FASEB J. 1999, 13, 9).

VEGF expression is reported to be induced by hypoxia (Shweiki et al.Nature 1992, 359, 843), as well as by a variety of cytokines and growthfactors, such as interleukin-1, interleukin-6, epidermal growth factorand transforming growth factor. To date, VEGF and the VEGF familymembers have been reported to bind to one or more of three transmembranereceptor tyrosine kinases (Mustonen et al. J. Cell Biol., 1995, 129,895), VEGF receptor-1 (also known as flt-1 (fms-like tyrosinekinase-1)), VEGFR-2 (also known as kinase insert domain containingreceptor (KDR); the murine analogue of KDR is known as fetal liverkinase-1 (flk-1)), and VEGFR-3 (also known as flt-4). KDR and fit-1 havebeen shown to have different signal transduction properties(Waltenberger et al. J. Biol. Chem. 1994, 269, 26988); Park et al.Oncogene 1995, 10, 135). Thus, KDR undergoes strong ligand-dependanttyrosine phosphorylation in intact cells, whereas flt-1 displays a weakresponse. Thus, binding to KDR is believed to be a critical requirementfor induction of the full spectrum of VEGF-mediated biologicalresponses.

In vivo, VEGF plays a central role in vasculogenesis, and inducesangiogenesis and permeabilization of blood vessels. Deregulated VEGFexpression contributes to the development of a number of diseases thatare characterized by abnormal angiogenesis and/or hyperpermeabilityprocesses. It is believed regulation of the VEGF-mediated signaltransduction cascade by some agents can provide a useful mode forcontrol of abnormal angiogenesis and/or hyperpermeability processes.

The vascular endothelial growth factors (VEGF, VEGF-C, VEGF-D) and theirreceptors (VEGFR2, VEGFR3) are not only key regulators of tumorangiogenesis, but also lymphangiogenesis. VEGF, VEGF-C and VEGF-D areexpressed in most tumors, primarily during periods of tumor growth and,often at substantially increased levels. VEGF expression is stimulatedby hypoxia, cytokines, oncogenes such as ras, or by inactivation oftumor suppressor genes (McMahon, G. Oncologist 2000, 5(Suppl. 1), 3-10;McDonald, N. Q.; Hendrickson, W. A. Cell 1993, 73, 421-424)

The biological activities of the VEGFs are mediated through binding totheir receptors. It is believed VEGFR3 (also called Flt-4) ispredominantly expressed on lymphatic endothelium in normal adult tissuesand that VEGFR3 function is needed for new lymphatic vessel formation,but not for maintenance of the pre-existing lymphatics. VEGFR3 is alsoupregulated on blood vessel endothelium in tumors. Recently VEGF-C andVEGF-D, ligands for VEGFR3, have been identified as regulators oflymphangiogenesis in mammals. Lymphangiogenesis induced bytumor-associated lymphangiogenic factors could promote the growth of newvessels into the tumor, providing tumor cells access to systemiccirculation. Cells that invade the lymphatics could find their way intothe bloodstream via the thoracic duct. Tumor expression studies haveallowed a direct comparison of VEGF-C, VEGF-D and VEGFR3 expression withclinicopathological factors that relate directly to the ability ofprimary tumors to spread (e.g., lymph node involvement, lymphaticinvasion, secondary metastases, and disease-free survival). In manyinstances, these studies demonstrate a statistical correlation betweenthe expression of lymphangiogenic factors and the ability of a primarysolid tumor to metastasize (Skobe, M. et al. Nature Med. 2001, 7(2),192-198; Stacker, S. A. et al. Nature Med. 2001, 7(2), 186-191; Makinen,T. et al. Nature Med. 2001, 7(2), 199-205; Mandriota, S. J. et al. EMBOJ. 2001, 20(4), 672-82; Karpanen, T. et al. Cancer Res. 2001, 61(5),1786-90; Kubo, H. et al. Blood 2000, 96(2), 546-53).

Hypoxia appears to be an important stimulus for VEGF production inmalignant cells. Activation of p38 MAP kinase is required for VEGFinduction by tumor cells in response to hypoxia (Blaschke, F. et al.Biochem. Biophys. Res. Commun. 2002, 296, 890-896; Shemirani, B. et al.Oral Oncology 2002, 38, 251-257). In addition to its involvement inangiogenesis through regulation of VEGF secretion, p38 MAP kinasepromotes malignant cell invasion, and migration of different tumor typesthrough regulation of collagenase activity and urokinase plasminogenactivator expression (Laferriere, J. et al. J. Biol. Chem. 2001, 276,33762-33772; Westermarck, J. et al. Cancer Res. 2000, 60, 7156-7162;Huang, S. et al. J. Biol. Chem. 2000, 275, 12266-12272; Simon, C. et al.Exp. Cell Res. 2001, 271, 344-355).

The receptor tyrosine kinase Trk-A is another target of interest for thepreparation of medicines directed at the treatment and prevention ofcancer. TrkA is the high affinity receptor of the nerve growth factor(NGF). The expression of TrkA and NGF in tumors is believed to beimplicated in the proliferation and metastasis of tumors such aspancreatic, prostate and also breast, as well as in angiogenesis. TrkAexpression is reported in pancreatic, breast, ovarian, and prostatetumors. Recent studies demonstrate that human prostate and pancreatictumor cells can secrete NGF, which, along with its receptor, TrkA,creates an autocrine loop that promotes the growth and survival of thesetumor cells (Ruggeri, B. A. et al, Curr. Med. Chem. 1999, 6:845-857;Weeraratna, A. T. et al., The Prostate 2000, 45:140-148). Inhibition ofthe NGF-TrkA signaling pathway by small molecule TrkA inhibitors(Miknyoczki, S. J. et al., Clin. Cancer Res. 1999, 5: 2205-2212; George,D. J. et al., Cancer Res. 1999, 59: 2395-2401; Weeraratna, A. T. et al,Clin. Cancer Res. 2001, 7: 2237-2245) and anti-NGF antibodies(Miknyoczki, S. J. et al., Clin. Cancer Res. 2002, 8:1924-1931) has beenpostulated to inhibit not only growth, but also metastasis ofneuroendocrine tumors in xenograft models. In addition, NGF has beenshown to induce proliferation of endothelial cells (Cantarella, G. etal., FASEB J. 2002, 16: 1307). These cells, which form new vascularnetworks to feed the growing tumor, also express VEGFR2 tyrosine kinasereceptors. Activation of these receptors by their ligands leads toendothelial cell proliferation, migration, and vessel formation andstabilization (Albo, D. et al., Curr. Pharm. Des. 2004, 10:27-37;Thurston, G., Cell Tissue Res. 2003, 31:61-68).

Certain diarylureas have been described as having activity asserine-threonine kinase and/or as tyrosine kinase inhibitors. Theultility of these diarylureas as an active ingredient in pharmaceuticalcompositions for the treatment of cancer, angiogenesis disorders, andinflammatory disorders has been demonstrated. See Redman et al., Bioorg.Med. Chem. Lett. 2001, 11, 9-12; Smith et al., Bioorg. Med. Chem. Lett.2001, 11, 2775-2778; Dumas et al., Bioorg. Med. Chem. Lett. 2000, 10,2047-2050; Dumas et al., Bioorg. Med. Chem. Lett. 2000, 10, 2051-2054;Ranges et al., Book of Abstracts, 220^(th) ACS National Meeting,Washington, D.C., USA, MEDI 149; Dumas et al., Bioorg. Med. Chem. Lett.2002, 12, 1559-1562; Lowinger et al., Clin. Cancer Res. 2000, 6(suppl.),335; Lyons et al., Endocr.-Relat. Cancer 2001, 8, 219-225; Riedl et al.,Book of Abstracts, 92^(nd) AACR Meeting, New Orleans, La., USA, abstract4956; Khire et al., Book of Abstracts, 93^(rd) AACR Meeting, SanFrancisco, Calif., USA, abstract 4211; Lowinger et al., Curr. Pharm.Design 2002, 8, 99-110; Regan et al., J. Med. Chem. 2002, 45, 2994-3008;Pargellis et al., Nature Struct. Biol. 2002, 9(4), 268-272; Carter etal., Book of Abstracts, 92^(nd) AACR Meeting, New Orleans, La., USA,abstract 4954; Vincent et al., Book of Abstracts, 38^(th) ASCO Meeting,Orlando, Fla., USA, abstract 1900; Hilger et al., Book of Abstracts,38^(th) ASCO Meeting, Orlando, Fla., USA, abstract 1916; Moore et al.,Book of Abstracts, 38^(th) ASCO Meeting, Orlando, Fla., USA, abstract1816; Strumberg et al., Book of Abstracts, 38^(th) ASCO Meeting,Orlando, Fla., USA, abstract 121; Madwed J B: Book of Abstracts, ProteinKinases: Novel Target Identification and Validation for TherapeuticDevelopment, San Diego, Calif., USA, March 2002; Roberts et al., Book ofAbstracts, 38^(th) ASCO Meeting, Orlando, Fla., USA, abstract 473;Tolcher et al., Book of Abstracts, 38^(th) ASCO Meeting, Orlando, Fla.,USA, abstract 334; and Karp et al., Book of Abstracts, 38^(th) AACRMeeting, San Francisco, Calif., USA, abstract 2753.

Despite the advancements in the art, there remains a need for cancertreatments and anti-cancer compounds.

DESCRIPTION OF THE INVENTION

The present invention pertains to:

(i) novel compounds of Formula I below, salts, metabolites and prodrugsthereof, including diastereoisomeric forms,(ii) pharmaceutical compositions containing compounds of Formula I belowor salts, metabolites or prodrugs thereof, including diastereoisomericforms, and(iii) use of those compounds of (i) or compositions of (ii) for treatingdiseases, e.g., hyper-proliferative and angiogenesis disorders, as asole agent or in combination with other active ingredients, e.g.,cytotoxic therapies.

The compounds of Formula I, salts, metabolites and prodrugs thereof,including diastereoisomeric forms (both isolated stereoisomers andmixtures of stereoisomers) are collectively referred to herein as the“compounds of the invention”. Formula I is as follows:

R¹ and R² are independently selected from:(a) hydrogen;(b) (C₁-C₅)alkyl, optionally substituted with one or more hydroxy orfluoro; or(c) halogen.

In a class of compounds of formula I, R¹ is (C₁-C₅)alkyl and R² ishydrogen. In a subclass of this class of compounds, R¹ is tert-butyl,isopropyl, or cyclopentyl and R² is hydrogen.

A is phenyl, pyridine, or pyrimidine, optionally substituted with 1 or 2substituents that are independently selected from (C₁-C₅)alkyl,(C₁-C₅)alkoxy, (C₁-C₅)haloalkyl, (C₁-C₅)haloalkoxy, or halogen.Structures for A of formula I which are of particular interest arephenyl and pyridine optionally substituted with 1 or 2 substituents thatare independently selected from (C₁-C₅)alkyl, (C₁-C₅)alkoxy or halogen.Included in the structures for A of formula I which are of particularinterest are structures of formulae 1x and 1xx:

wherein R^(a) is methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,bromine, chlorine or fluorine.

The structures 1x and 1xx represent that the substituents R^(a) and thegroup —(CH₂)_(n)—X—Y can appear on any carbon atom in the ring which hasa valence that is otherwise complete with a hydrogen atom as asubstituent. The bond to the pyrazole ring can also be through anycarbon atom in the ring which has a valence that is otherwise completewith a hydrogen atom as a substituent.

In a class of compounds of formula I, the pyrazole ring and the group,—(CH₂)_(n)—X—Y are not bound to contiguous ring carbons of A, but ratherhave 1 or 2 ring carbons separating them.

B is phenylene or naphthylene, optionally substituted with 1 to 4substituents that are independently selected from (C₁-C₅)alkyl,(C₁-C₅)alkoxy, (C₁-C₅)haloalkyl, (C₁-C₅)haloalkoxy, or halogen. In aclass of compounds of formula I, B is phenylene, optionally substitutedwith 1 to 2 halogen atoms. Structures for B of formula (I) includedwithin this class are those of formula 2x:

wherein R^(b) is fluorine or chlorine.

The structure 2x represents that the substituents R^(b) can appear onany carbon atom in the ring which has a valence that is otherwisecomplete with a hydrogen atom as a substituent. In addition, both thebond to the urea group, —NH—C(O)—NH—, and the bond to the bridginggroup, L, can be through any carbon atom in the ring which has a valencethat is otherwise complete with a hydrogen atom as a substituent.

In a class of compounds of formula (I), the urea group —NH—C(O)—NH— andthe bridging group, L, are not bound to contiguous ring carbons of B,but rather have 1 or 2 ring carbons separating them.

A class of structures of interest for B of formula (I) are of thefollowing formulae:

L is a bridging group which is —O—, —S—, or —CH₂—. In a class ofcompounds of formula I, L is —O—.

M is phenyl, pyridine or pyrimidine, optionally substituted with 1 to 3substituents that are independently selected from:

(1) (C₁-C₅)alkyl;(2) (C₁-C₅)haloalkyl;

(3) —O—R³; (4) —NR³R⁴;

(5) halogen;

(6) —C(O)NR³R⁴;

(7) cyano;

(8) C(O)R³; (9) —C≡C—R³; or

(10) nitro.

In a class of compounds of formula I, M is pyridine, optionallysubstituted with 1 substituent selected from:

(1) (C₁-C₅)alkyl;(2) (C₁-C₅)haloalkyl;

(3) —O—R³; (4) —NR³R⁴;

(5) halogen;

(6) —C(O)NR³R⁴;

(7) cyano;

(8) C(O)R³; (9) —C≡C—R³; or

(10) nitro.

A subclass of optionally substituted pyridine structures for M offormula (I) are of the following formulae:

wherein R^(c) is (C₁-C₅)alkyl; (C₁-C₅)haloalkyl; —O—R³; —NR³R⁴; halogen;—C(O)NR³R⁴; cyano C(O)R³; —C≡C—R³ or nitro.

In formula I, n is zero or one and

X is: (1) —O—; (2) —SO₂—; (3) —NR⁵—; (4) —NR⁵—SO₂—; (5) —N(SO₂NR⁷R⁸)—;(6) —SO₂—NR⁵—; (7) —NR⁵—C(O)—; (8) —C(O)—NR⁵—; (9) —C(O)—; or

(10) a single bond.

In a class of compounds of formula I, X is —O—; —NR⁵—; —NR⁵—C(O)—;—C(O)—NR⁵— or a single bond.

In formula I above, Y is a linear or branched C₁ to C₆ alkyl fragmentthat is substituted with one or two Z groups, where each Z group isindependently selected from:

(1) —OR⁶; (2) —O—C(O)—R⁶; (3) —NR⁷R⁸;

(4) —SO₂—(C₁-C₅)alkyl;

(5) —C(O)—O—R⁶; (6) —NH—C(O)—R⁶; (7) —C(O)—NR⁷R⁸; or

(8) a monocyclic, saturated, partially saturated, or aromaticheterocycle of 5-7 ring atoms containing at least one heteroatomselected from N, O, or S, that is optionally substituted with 1 to 3substituents selected from (C₁-C₅)alkyl, (C₁-C₅)haloalkyl, hydroxy,amino, halogen, or oxo;with the proviso that when n is zero and X is —O—, —NR³—, or a singlebond, then Z is not morpholine, piperidine, imidazole, or tetrazole;with the further proviso that when n is zero and X is a single bond,then Z is not —NR⁷R⁸.

In a class of compounds of formula I, Y is a linear or branched C₁ to C₄alkyl fragment (C₁ to C₄ alkyl chain) that is substituted with one Zgroup selected from —OR⁶; —NR⁷R⁸; —NH—C(O)—R⁶ or —C(O)—NR⁷R⁸. In asubclass of compounds of this invention within this class, Y ismethylene, ethylene, n-propylene or n-butylene.

The substituents R³, R⁴, R⁵ and R⁶ are each independently hydrogen or(C₁-C₅)alkyl optionally substituted with hydroxy. In a class ofcompounds of this invention, R³, R⁴, R⁵ and R⁶ are each independentlyhydrogen, methyl, ethyl, propyl or butyl, optionally substituted withhydroxy.

The substituents R⁷ and R⁸ are independently hydrogen, or (C₁-C₅)alkyloptionally substituted with hydroxy; or the group —NR⁷R⁸ forms amonocyclic saturated heterocyclic ring having 5 to 7 ring atoms, where,in addition to the nitrogen atom attached to the rest of the molecule,zero to two of the other ring atoms is a hetero atom selected from N, Oand S, and the remaining ring atoms are carbon. Examples of such —NR⁷R⁸monocyclic saturated heterocyclic ring groups include pyrrolidine,piperidine, azepane, morpholine, thiomorpholine, piperazine, andhomopiperazine. The —NR⁷R⁸ monocyclic saturated heterocyclic ring groupis optionally substituted on a carbon atom with hydroxy.

In a class of compounds of formula I, R⁷ and R⁸ are each independentlyhydrogen, methyl, ethyl, propyl or butyl, optionally substituted withhydroxy.

A class of compounds of this invention within the scope of Formula I arealso of Formula II, including the salts, metabolites and prodrugsthereof and diastereoisomeric forms (both isolated stereoisomers andmixtures of stereoisomers) thereof. Formula II is as follows:

wherein R^(b) is fluorine or chlorine andR¹ and R² are independently selected from:(a) hydrogen;(b) (C₁-C₅)alkyl, optionally substituted with one or more hydroxy orfluoro; or(c) halogen.

In a class of compounds of formula II, R¹ is (C₁-C₅)alkyl and R² ishydrogen. In a subclass of this class of compounds, R¹ is tert-butyl,isopropyl, or cyclopentyl and R² is hydrogen.

A is phenyl, pyridine, or pyrimidine, optionally substituted with 1 or 2substituents that are independently (C₁-C₅)alkyl, (C₁-C₅)alkoxy,(C₁-C₅)haloalkyl, (C₁-C₅)haloalkoxy, or halogen. In a class of compoundsof formula II, Structures for A are phenyl and pyridine optionallysubstituted with 1 or 2 substituents that are independently(C₁-C₅)alkyl, (C₁-C₅)alkoxy or halogen.

Structures of optionally substituted phenyl or pyridinyl moieties for Aof formula II which are of particular interest include structures offormulae 1x and 1xx:

wherein R^(a) is methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,bromine, chorine or fluorine.

The structures 1x and 1xx represent that the substituents R^(a) and thegroup —(CH₂)_(n)—X—Y can appear on any carbon atom in the ring which hasa valence that is otherwise complete with a hydrogen atom as asubstituent. The bond to the pyrazole ring can also be through anycarbon atom in the ring which has a valence that is otherwise completewith a hydrogen atom as a substituent.

In a class of compounds of formula II, the pyrazole ring and the group,—(CH₂)_(n)—X—Y are not bound to contiguous ring carbons of A, but ratherhave 1 or 2 ring carbons separating them.

Formula II represents that the substituents R^(b) can appear on anycarbon atom in the phenyl ring which has a valence that is otherwisecomplete with a hydrogen atom as a substituent. The following structuresillustrate the positions for R^(b) which are of interest:

R^(c) is selected from:(1) (C₁-C₅)alkyl;(2) (C₁-C₅)haloalkyl;

(3) —O—R³; (4) —NR³R⁴;

(5) halogen;

(6) —C(O)NR³R⁴;

(7) cyano;

(8) C(O)R³; (9) —C≡C—R³; or

(10) nitro.

Structures which illustrate positions for R^(c) which are of interestare as follows:

In formula II, n is zero or one and

X is: (1) —O—; (2) —SO₂—; (3) —NR⁵—; (4) —NR⁵—SO₂—; (5) —N(SO₂NR⁷R⁸)—;(6) —SO₂—NR⁵—; (7) —NR⁵—C(O)—; (8) —C(O)—NR⁵—; (9) —C(O)—; or

(10) a single bond.

In a class of compounds of formula II, X is —O—; —NR⁵—; —NR⁵—C(O)—;—C(O)—NR⁵— or a single bond.

In formula II above, Y is a linear or branched C₁ to C₆ alkyl fragmentthat is substituted with one or two Z groups, where each Z group isindependently selected from:

(1) —OR⁶; (2) —O—C(O)—R⁶; (3) —NR⁷R⁸;

(4) —SO₂—(C₁-C₅)alkyl;

(5) —C(O)—O—R⁶; (6) —NH—C(O)—R⁶; (7) —C(O)—NR⁷R⁸; or

(8) a monocyclic, saturated, partially saturated, or aromaticheterocycle of 5-7 ring atoms containing at least one heteroatomselected from N, O, or S, that is optionally substituted with 1 to 3substituents selected from (C₁-C₅)alkyl, (C₁-C₅)haloalkyl, hydroxy,amino, halogen, or oxo;with the proviso that when n is zero and X is —O—, —NR³—, or a singlebond, then Z is not morpholine, piperidine, imidazole, or tetrazole;with the further proviso that when n is zero and X is a single bond,then Z is not —NR⁷R⁸.

In a class of compounds of formula II, Y is a linear or branched C₁ toC₄ alkyl fragment (C₁ to C₄ alkyl chain) that is substituted with one Zgroup selected from —OR⁶; —NR⁷R⁸; —NH—C(O)—R⁶ or —C(O)—NR⁷R⁸. In asubclass of compounds of this invention within this class, Y ismethylene, ethylene, n-propylene or n-butylene.

The substituents R³, R⁴, R⁵ and R⁶ are each independently hydrogen or(C₁-C₅)alkyl optionally substituted with hydroxy. In a class ofcompounds of this invention, R³, R⁴, R⁵ and R⁶ are each independentlyhydrogen, methyl, ethyl, propyl or butyl, optionally substituted withhydroxy.

The substituents R⁷ and R⁸ are independently hydrogen, or (C₁-C₅)alkyloptionally substituted with hydroxy; or the group —NR⁷R⁸ forms amonocyclic saturated heterocyclic ring having 5 to 7 ring atoms, where,in addition to the nitrogen atom attached to the rest of the molecule,zero to two of the other ring atoms is a hetero atom selected from N, Oand S, and the remaining ring atoms are carbon. Examples of such —NR⁷R⁸monocyclic saturated heterocyclic ring groups include pyrrolidine,piperidine, azepane, morpholine, thiomorpholine, piperazine, andhomopiperazine. The —NR⁷R⁸ monocyclic saturated heterocyclic ring groupis optionally substituted on a carbon atom with hydroxy.

In a class of compounds of formula II, R⁷ and R⁸ are each independentlyhydrogen, methyl, ethyl, propyl or butyl, optionally substituted withhydroxy.

A class of compounds of this invention are within the scope of formulaeI and II and the scope of formulae III and IV, including the salts,metabolites and prodrugs thereof and diastereoisomeric forms (bothisolated stereoisomers and mixtures of stereoisomers) thereof. FormulaIII and IV are as follows:

wherein R^(a) is methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,bromine, chorine or fluorine;R^(c) is (C₁-C₅)alkyl; (C₁-C₅)haloalkyl; —O—R³; —NR³R⁴; halogen;—C(O)NR³R⁴; cyano; C(O)R³; —C≡C—R³; or nitro; andR^(z) is tert-butyl, isopropyl, or cyclopentyl.

Formulae III and IV each represent that the fluorine substituent canappear on any carbon atom in the ring which has a valence that isotherwise complete with a hydrogen atom as a substituent. The followingstructures illustrate the positions for fluorine substituent which areof interest:

A subclass of optionally substituted pyridine structures for M offormula (I) are of the following formulae:

In formulae III and IV, n is zero or one and

X is: (1) —O—; (2) —SO₂—; (3) —NR⁵—; (4) —NR⁵—SO₂—; (5) —N(SO₂NR⁷R⁸)—;(6) —SO₂—NR⁵—; (7) —NR⁵—C(O)—; (8) —C(O)—NR⁵—; (9) —C(O)—; or

(10) a single bond.

In a class of compounds of formulae III and IV, X is —O—; —NR⁵—;—NR⁵—C(O)—; —C(O)—NR⁵— or a single bond.

In formulae III and IV above, Y is a linear or branched C₁ to C₆ alkylfragment that is substituted with one or two Z groups, where each Zgroup is independently selected from:

(1) —OR⁶; (2) —O—C(O)—R⁶; (3) —NR⁷R⁸;

(4) —SO₂—(C₁-C₅)alkyl;

(5) —C(O)—O—R⁶; (6) —NH—C(O)—R⁶; (7) —C(O)—NR⁷R⁸; or

(8) a monocyclic, saturated, partially saturated, or aromaticheterocycle of 5-7 ring atoms containing at least one heteroatomselected from N, O, or S, that is optionally substituted with 1 to 3substituents selected from (C₁-C₅)alkyl, (C₁-C₅)haloalkyl, hydroxy,amino, halogen, or oxo;with the proviso that when n is zero and X is —O—, —NR³—, or a singlebond, then Z is not morpholine, piperidine, imidazole, or tetrazole;with the further proviso that when n is zero and X is a single bond,then Z is not —NR⁷R⁸.

In a class of compounds of formulae III and IV, Y is a linear orbranched C₁ to C₄ alkyl fragment (C₁ to C₄ alkyl chain) that issubstituted with one Z group selected from —OR⁶; —NR⁷R⁸; —NH—C(O)—R⁶ or—C(O)—NR⁷R⁸. In a subclass of compounds of this invention within thisclass, Y is methylene, ethylene, n-propylene or n-butylene.

The substituents R³, R⁴, R⁵ and R⁶ are each independently hydrogen or(C₁-C₅)alkyl optionally substituted with hydroxy. In a class ofcompounds of this invention, R³, R⁴, R⁵ and R⁶ are each independentlyhydrogen, methyl, ethyl, propyl or butyl, optionally substituted withhydroxy.

The substituents R⁷ and R⁸ are independently hydrogen, or (C₁-C₅)alkyloptionally substituted with hydroxy; or the group —NR⁷R⁸ forms amonocyclic saturated heterocyclic ring having 5 to 7 ring atoms, where,in addition to the nitrogen atom attached to the rest of the molecule,zero to two of the other ring atoms is a hetero atom selected from N, Oand S, and the remaining ring atoms are carbon. Examples of such —NR⁷R⁸monocyclic saturated heterocyclic ring groups include pyrrolidine,piperidine, azepane, morpholine, thiomorpholine, piperazine, andhomopiperazine. The —NR⁷R⁸ monocyclic saturated heterocyclic ring groupis optionally substituted on a carbon atom with hydroxy.

In a class of compounds of formulae III and IV I of particular interest,R⁷ and R⁸ are each independently selected from hydrogen, methyl, ethyl,propyl or butyl, optionally substituted with hydroxy.

Another class of compounds of this invention within the scope of formulaI are of Formulae V and VI, including the salts, metabolites andprodrugs thereof and diastereoisomeric forms (both isolatedstereoisomers and mixtures of stereoisomers) thereof. Formula V and VIare as follows:

whereinHal is bromine, chorine or fluorine; n is zero or one;X is: —O—; —NR⁵—; —NR⁵—C(O)—; —C(O)—NR⁵— or a single bond; andY is: methylene, ethylene, n-propylene or n-butylene substituted withone Z group which is: —OR⁶; —NR⁷R⁸; —NH—C(O)—R⁶ or —C(O)—NR⁷R⁸;with the proviso that when n is zero and X is a single bond, then Z isnot —NR⁷R⁸.

The substituents R⁵ and R⁶ are each independently hydrogen, methyl,ethyl, propyl or butyl, optionally substituted with hydroxy.

The substituents R⁷ and R⁸ are each independently hydrogen, methyl,ethyl, propyl or butyl, optionally substituted with hydroxy.

When any moiety is “substituted”, it can have up to the highest numberof indicated substituents, and each substituent can be located at anyavailable position on the moiety and can be attached through anyavailable atom on the substituent. “Any available position” means anyposition on the moiety that is chemically accessible through means knownin the art or taught herein and that does not create an unduly unstablemolecule. When there are two or more substituents on any moiety, eachsubstituent is defined independently of any other substituent and can,accordingly, be the same or different.

The term “optionally substituted” means that the moiety so modified maybe either unsubstituted, or substituted with the identifiedsubstituent(s).

It is understood that if M is pyridine, the term “OR⁴”, combined withR⁴═H, represents a 2-, 3-, and 4-hydroxypyridine, but also includesthose structures referred to in the art as 1-oxo-pyridine,1-hydroxy-pyridine and pyridine N-oxide. The same applies if M is apyrimidine ring.

Where the plural form of the word compounds, salts, and the like, isused herein, this is taken to mean also a single compound, salt, or thelike.

The term (C₁-C₅)alkyl, means straight, branched, or cyclic alkyl groupshaving from one to five carbon atoms, that may be linear or branchedwith single or multiple branching. Such groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,cyclobutyl, 1-methylcyclopropyl, and the like.

The term (C₁-C₅)haloalkyl means a (C₁-C₅)alkyl group as defined above,that is substituted with a least one halogen atom, up to per-halo. Thehalo substituent(s) include fluoro, chloro, bromo, or iodo. Fluoro,chloro and bromo are preferred, and fluoro and chloro are morepreferred. The halogen substituent(s) can be located on any availablecarbon. When more than one halogen substituent is present on thismoiety, they may be the same or different carbon atoms. Examples of suchhalogenated alkyl substituents include but are not limited tochloromethyl, dichloromethyl, trichloromethyl, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and1,1,2,2-tetrafluoroethyl, and the like.

The term (C₁-C₅)alkoxy means a straight, branched, or cyclic alkoxygroup having from one to three saturated carbon atoms that may be linearor branched with single or multiple branching, and includes such groupsas methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy,cyclobutylmethoxy, and the like.

The term (C₁-C₅)haloalkoxy means a (C₁-C₅)alkoxy group as defined above,that is substituted with at least one halogen atom, up to per-halo, andincludes halogenated groups such as 2,2-dichloroethoxy,trifluoromethoxy, and the like.

Halogen means fluoro, chloro, bromo, or iodo. Fluoro, chloro and bromoare preferred, and fluoro and chloro are more preferred.

The term “monocyclic, saturated, partially saturated, or aromaticheterocycle containing at least one heteroatom selected from N, O, or S”refers to a synthetically accessible, saturated, partially saturated, oraromatic monocyclic ring having 5 to 7 ring atoms, where one to three ofthese ring atoms is a hetero atom selected from N, O and S, with theremaining ring atoms being carbon. When more than one hetero atom ispresent in the moiety, they are selected independently from the other(s)so that they may be the same or different. Saturated heterocyclic ringsinclude, but are not limited to, tetrahydropyrane, pyrrolidine,piperidine, azepane, morpholine, thiomorpholine, tetrahydrofuran,tetrahydrothiophene, oxetane, dioxane, and the like. Partially saturatedheterocyclic rings include, but are not limited to, dihydrofurane,dihydropyrane, dihydropyridine, dihydrothiophene, and the like.Monocyclic aromatic heterocyclic rings include, but are not limited topyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole,isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole,pyridine, pyrimidine, pyridazine, pyrazine, and triazine.

The compounds of Formula I may contain one or more asymmetric centers,depending upon the location and nature of the various substituentsdesired. Asymmetric carbon atoms may be present in the (R) or (S)configuration or (R,S) configuration. In certain instances, asymmetrymay also be present due to restricted rotation about a given bond, forexample, the central bond adjoining two substituted aromatic rings ofthe specified compounds. Substituents on a ring may also be present ineither cis or trans form. It is intended that all such configurations(including enantiomers and diastereomers), are included within the scopeof the present invention. Preferred compounds are those with theabsolute configuration of the compound of Formula I which produces themore desirable biological activity. Separated, pure or partiallypurified isomers or racemic mixtures of the compounds of this inventionare also included within the scope of the present invention. Thepurification of said isomers and the separation of said isomericmixtures can be accomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical and/orchemical differences by methods known in the art, for example, bychromatography or fractional crystallization. The optically active basesor acids are then liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofchiral chromatography (e.g., chiral HPLC columns), with or withoutconventional derivation, optimally chosen to maximize the separation ofthe enantiomers. Suitable chiral HPLC columns are manufactured byDiacel, e.g., Chiracel OD and Chiracel OJ among many others, allroutinely selectable. Enzymatic separations, with or withoutderivitization, are also useful. The optically active compounds ofFormula I can likewise be obtained by chiral syntheses utilizingoptically active starting materials.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as pharmaceutically acceptable salts, metabolitesand prodrugs of all the compounds Formula (I). The term“pharmaceutically acceptable salt” refers to a relatively non-toxic,inorganic or organic acid addition salt of a compound of the presentinvention. For example, see S. M. Berge, et al. “Pharmaceutical Salts,”J. Pharm. Sci. 1977, 66, 1-19. Pharmaceutically acceptable salts includethose obtained by reacting the main compound, functioning as a base,with an inorganic or organic acid to form a salt, for example, salts ofhydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonicacid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid andcitric acid. Pharmaceutically acceptable salts also include those inwhich the main compound functions as an acid and is reacted with anappropriate base to form, e.g., sodium, potassium, calcium, magnesium,ammonium, and chorine salts. Those skilled in the art will furtherrecognize that acid addition salts of the claimed compounds may beprepared by reaction of the compounds with the appropriate inorganic ororganic acid via any of a number of known methods. Alternatively, alkaliand alkaline earth metal salts are prepared by reacting the compounds ofthe invention with the appropriate base via a variety of known methods.

Representative salts of the compounds of this invention include theconventional non-toxic salts and the quaternary ammonium salts which areformed, for example, from inorganic or organic acids or bases by meanswell known in the art. For example, such acid addition salts includeacetate, adipate, alginate, ascorbate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate,maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate,nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate,tartrate, thiocyanate, tosylate, and undecanoate.

Base salts include alkali metal salts such as potassium and sodiumsalts, alkaline earth metal salts such as calcium and magnesium salts,and ammonium salts with organic bases such as dicyclohexylamine andN-methyl-D-glucamine. Additionally, basic nitrogen containing groups maybe quaternized with such agents as lower alkyl halides such as methyl,ethyl, propyl, and butyl chlorides, bromides and iodides; dialkylsulfates like dimethyl, diethyl, and dibutyl sulfate; and diamylsulfates, long chain halides such as decyl, lauryl, myristyl andstrearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others.

Certain compounds of this invention can be further modified with labilefunctional groups that are cleaved after in vivo administration tofurnish the parent active agent and the pharmacologically inactivederivatizing (functional) group. These derivatives, commonly referred toas prodrugs, can be used, for example, to alter the physicochemicalproperties of the active agent, to target the active agent to a specifictissue, to alter the pharmacokinetic and pharmacodynamic properties ofthe active agent, and to reduce undesirable side effects

Prodrugs of the invention include, e.g., the esters of appropriatecompounds of this invention, are well-tolerated, pharmaceuticallyacceptable esters such as alkyl esters including methyl, ethyl, propyl,isopropyl, butyl, isobutyl or pentyl esters. Additional esters such asphenyl(C₁-C₅)alkyl may be used, although methyl ester is preferred.

Methods for synthesizing prodrugs are described in the following reviewson the subject, which are incorporated herein by reference for theirdescription of these methods:

-   Higuchi, T.; Stella, V. eds. Prodrugs As Novel Drug Delivery    Systems. ACS Symposium Series. American Chemical Society:    Washington, D.C. (1975).-   Roche, E. B. Design of Biopharmaceutical Properties through Prodrugs    and Analogs. American Pharmaceutical Association: Washington, D.C.    (1977).-   Sinkula, A. A.; Yalkowsky, S. H. J Pharm Sci. 1975, 64, 181-210.-   Stella, V. J.; Charman, W. N. Naringrekar, V. H. Drugs 1985, 29,    455-473.-   Bundgaard, H., ed. Design of Prodrugs. Elsevier: New York (1985).-   Stella, V. J.; Himmelstein, K. J. J. Med. Chem. 1980, 23, 1275-1282.-   Han, H-K; Amidon, G. L. AAPS Pharmsci 2000, 2, 1-11.-   Denny, W. A. Eur. J. Med. Chem. 2001, 36, 577-595.-   Wermuth, C. G. in Wermuth, C. G. ed. The Practice of Medicinal    Chemistry Academic Press: San Diego (1996), 697-715.-   Balant, L. P.; Doelker, E. in Wolff, M. E. ed. Burgers Medicinal    Chemistry And Drug Discovery John Wiley & Sons: New York (1997),    949-982.

General Preparative Methods

The particular process to be utilized in the preparation of thecompounds used in this embodiment of the invention depends upon thespecific compound desired. Such factors as the selection of the specificsubstituents play a role in the path to be followed in the preparationof the specific compounds of this invention. Those factors are readilyrecognized by one of ordinary skill in the art.

The compounds of the invention may be prepared by use of known chemicalreactions and procedures. Nevertheless, the following generalpreparative methods are presented to aid the reader in synthesizing thecompounds of the present invention, with more detailed particularexamples being presented below in the experimental section describingthe working examples.

All variable groups of these methods are as described in the genericdescription if they are not specifically defined below. When a variablegroup or substituent with a given symbol is used more than once in agiven structure, it is to be understood that each of these groups orsubstituents may be independently varied within the range of definitionsfor that symbol. It is recognized that compounds of the invention witheach claimed optional functional group cannot be prepared with each ofthe below-listed methods. Within the scope of each method optionalsubstituents are used which are stable to the reaction conditions, orthe functional groups which may participate in the reactions are presentin protected form where necessary, and the removal of such protectivegroups is completed at appropriate stages by methods well known to thoseskilled in the art.

The compounds of the invention can be made according to conventionalchemical methods, and/or as disclosed below, from starting materialswhich are either commercially available or producible according toroutine, conventional chemical methods. General methods for thepreparation of the compounds are given below, and the preparation ofrepresentative compounds is specifically illustrated in examples.

Specific preparations of diaryl ureas, including pyrazolyl ureas, arealready described in the patent literature, and can be adapted to thecompounds of the present invention. For example, Miller S. et al,“Inhibition of p38 Kinase using Symmetrical and Unsymmetrical DiphenylUreas” PCT Int. Appl. WO 99 32463, Miller, S et al. “Inhibition of rafKinase using Symmetrical and Unsymmetrical Substituted Diphenyl Ureas”PCT Int. Appl., WO 99 32436, Dumas, J. et al., “Inhibition of p38 KinaseActivity using Substituted Heterocyclic Ureas” PCT Int. Appl., WO 9932111, Dumas, J. et al., “Method for the Treatment of Neoplasm byInhibition of raf Kinase using N-Heteroaryl-N′-(hetero)arylureas” PCTInt, Appl., WO 99 32106, Dumas, J. et al., “Inhibition of p38 KinaseActivity using Aryl- and Heteroaryl-Substituted Heterocyclic Ureas” PCTInt. Appl., WO 99 32110, Dumas, J., et al., “Inhibition of raf Kinaseusing Aryl- and Heteroaryl-Substituted Heterocyclic Ureas” PCT Int.Appl., WO 99 32455, Riedl, B., et al., “O-Carboxy Aryl SubstitutedDiphenyl Ureas as raf Kinase Inhibitors” PCT Int. Appl., WO 00 42012,Riedl, B., et al., “O-Carboxy Aryl Substituted Diphenyl Ureas as p38Kinase Inhibitors” PCT Int. Appl., WO 00 41698, Dumas, J. et al.“Heteroaryl ureas containing nitrogen hetero-atoms as p38 kinaseinhibitors” U.S. Pat. Appl. Publ., US 20020065296, Dumas, J. et al.“Preparation of N-aryl-N′-[(acylphenoxy)phenyl]ureas as raf kinaseinhibitors” PCT Int. Appl., WO 02 62763, Dumas, J. et al. “Inhibition ofraf kinase using quinolyl, isoquinolyl or pyridyl ureas” PCT Int. Appl.,WO 02 85857, Dumas, J. et al. “Preparation of quinolyl, isoquinolyl orpyridyl-ureas as inhibitors of raf kinase for the treatment of tumorsand/or cancerous cell growth” U.S. Pat. Appl. Publ., US 20020165394. Allthe preceding patent applications are hereby incorporated by reference.

The compounds of Formula I can be synthesized according to the reactionsequence shown in the General Method 1. These compounds can besynthesized by reacting arylamines of Formula III with isocyanates ofFormula II.

General Method 1

Compounds of Formula II can be synthesized according to methods commonlyknown to those skilled in the art. For example, isocyanates of FormulaII may be prepared in situ or isolated from treatment of amino-pyrazolesof Formula IV with phosgene or a phosgene equivalent such astrichloromethyl chloroformate (diphosgene),bis(trichloromethyl)carbonate (triphosgene), or N,N′-carbonyldiimidazole(CDI), or N,N′-carbonylditriazole (CDT). Alternatively, compounds ofFormula II can be obtained from the corresponding pyrazole-carboxylicacid derivatives via a Curtius-type rearrangement.

Aromatic amines of Formula III are commercially available or can besynthesized according methods commonly known to those skilled in theart. In particular, a large variety of aromatic amines of Formula IIIhas been described in the diaryl urea patent literature cited above.

Alternatively, compounds of Formula I can be prepared according toGeneral Method 2, where 3-aminopyrazoles of Formula IV and aminocompounds of Formula III are coupled together to form a urea of FormulaI. This process occurs in the presence of a coupling agent such ascarbonyldiimidazole, carbonylditriazole, phosgene, diphosgene,triphosgene, and the like. In this process, the isocyanates of FormulaII may or may not be formed during the reaction process. The couplingstep may be performed in an inert solvent such as dioxane, diethylether,dichloromethane, chloroform, tetrahydrofuran, toluene, and the like, ata temperature selected between 0° C. and reflux. This coupling may beachieved using these reagents alone, or in the presence of an organic orinorganic base as described in the art.

General Method 2

The reaction of the compounds of Formula II with aromatic amines ofFormula III is carried out preferably in a solvent. Suitable solventscomprise the customary organic solvents that are inert under thereaction conditions. Non-limiting examples include ethers such asdiethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxy ethane;hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane,mineral oil fractions; halogenated hydrocarbons such as dichloromethane,trichloromethane, carbon tetrachloride, dichloroethane,trichloroethylene, chlorobenzene; alcohols such as methanol, ethanol,n-propanol, isopropanol; esters such as ethyl acetate; ketones such asacetone; nitriles such as acetonitrile; heteroaromatics such aspyridine; polar solvents such as dimethyl formamide and hexamethylphosphoric acid tris-amide; and mixtures of the above-mentionedsolvents. Toluene, benzene, and dichloromethane are preferred.

Aromatic amines of Formula III are generally employed in an amount offrom 1 to 3 mol per mol of compounds of Formula II; an equimolar amountor slight excess of compounds of Formula III is preferred.

The reaction of the compounds of Formula II with aromatic amines ofFormula III is generally carried out within a relatively widetemperature range. In general, they are carried out in a range of from−20 to 200° C., preferably from 0 to 100° C., and more preferably from25 to 50° C. The steps of this reaction are generally carried out underatmospheric pressure. However, it is also possible to carry them outunder super-atmospheric pressure or at reduced pressure (for example, ina range of from 0.5 to 5 bar). The reaction time can generally be variedwithin a relatively wide range. In general, the reaction is finishedafter a period of from 2 to 24 hours, preferably from 6 to 12 hours.

3-Aminopyrazoles of Formula IV can be prepared by a variety of methodswhich will depend on the value of n and the nature of the X and Y linkerunits, as well as the nature of the Z substituent group(s) on Y.

For example, aminopyrazoles of Formula IV used for the preparation ofcompounds of Formula I where n=0 or 1 and X is —C(O)—NR⁵— can beprepared as follows. Carboxylic acids of Formula V are condensed withcyanoketones of Formula VI to afford aminopyrazole intermediates ofFormula VII, which are further derivatized by amide formation toaminopyrazoles of Formula IV where n=0 or 1 and X is —C(O)—NR⁵—, usingconventional methods.

Alternatively, use of an ester of Formula VIII would lead to anaminopyrazole of Formula IX, which can be amidated using an amine ofFormula Y—N(R⁵)H, for example in the presence of trimethylaluminum in aninert solvent. The compounds of Formula V and VIII are commerciallyavailable or are prepared by methods described in the scientificliterature; for example, an aryl amine H₂N-A-(CH₂)_(n)—CO₂R can betreated with sodium nitrite and then with tin(II) chloride under acidicconditions to provide the corresponding aryl hydrazine of Formula VIII.

Aminopyrazoles of Formula IV where n=0 and X is —NR⁵— or —NR⁵—C(O)— canbe prepared in several conventional steps as follows.Nitroaryl-hydrazines of Formula X can be condensed to aminopyrazoles ofFormula XI, which are reduced to the corresponding arylamines of FormulaXII (for example, via catalytic hydrogenation, or with the use of ironpowder in acetic acid, tin dichloride in DMF, or a similar reducingreagent known in the art). Intermediates of Formula XII can be furtherelaborated by amide formation with a carboxylic acid such as Y—COOH anda suitable coupling agent to give pyrazoles of Formula IV where n=0 andX is —NR⁵—C(O)—. Reduction of these compounds provides pyrazoles ofFormula IV where n=0 and X is —NR⁵—. Alternatively, reductive aminationof intermediates of Formula XII with an aldehyde also provides pyrazolesof Formula IV where n=0 and X is —NR⁵— as indicated below.

Coupling of aminopyrazoles of Formula XII with sulfonyl chlorides suchas Y—SO₂Cl, usually under basic conditions, provides aminopyrazoles ofFormula IV where n=0 and X is —NH—SO₂—. These sulfonamides may befurther alkylated with a halide reagent such as R⁵—Br, usually underbasic conditions, to give aminopyrazoles of Formula IV where X is—NR⁵—SO₂—.

Aminopyrazoles of Formula IV where n=0 and X is —O— can be prepared inseveral conventional steps as follows. Methoxy-aryl-hydrazines ofFormula XIII can be condensed to aminopyrazoles of Formula XIV, whichare de-methylated to the corresponding hydroxy compounds of Formula XV(for example, with the use of boron tribromide, methylthiolate in DMF,lithium diphenylphosphide, or an equivalent reagent known in the art).Intermediates of Formula XV can be further elaborated by alkylation, forexample with an alkyl halide such as Y—Br, Y—I, or Y—Cl or by aMitsunobu reaction with an alkanol such as Y—OH, to affordaminopyrazoles of Formula IV where n=0 and X is —O—.

Aminopyrazoles of Formula IV where n=0 and X is —SO₂NR⁵— can be preparedby standard methods as follows. Bromo-aryl-sulfonyl chlorides of FormulaXVI can be converted by reaction with an amine YN(R⁵)H to formbromo-aryl-sulfonamides of Formula XVII, which are then reacted with ahydrazone such as benzophenone

hydrazone to form the compounds of Formula XVIII. Condensation withcyanoketones of Formula VI provides the desired aminopyrazoles ofFormula IV where n=0 and X is —SO₂NR⁵—.

The synthetic transformations described above, which focus on theelaboration of the —X—Y chain, are meant to be applied to prepare3-aminopyrazole intermediates of Formula IV. However, in many cases, itis also possible to carry out the urea formation at an early stage inthe synthesis to lead to key urea intermediates of Formulas IX to XXII.Then, these urea intermediates can be subjected to additional reactionsto form the desired —X—Y chains, according to methods similar to thosedescribed above.

For example, compounds of Formula I where n=0 and X is —NR⁵— or—NR⁵—C(O)— can be prepared as indicated below. In this case, a compoundof Formula XXIII in which the group A is substituted with a nitrofunctionality is reduced (for example, by hydrogenation catalyzed bypalladium on carbon) to provide the related amino-substituted compoundof Formula XXIV. Intermediates of Formula XXIV can be further elaboratedby amide formation with a carboxylic acid such as Y—COOH and a suitablecoupling agent to give pyrazoles of Formula I where n=0 and X is—NR⁵—C(O)—. Reduction of these compounds provides pyrazoles of Formula Iwhere n=0 and X is —NR⁵—. Alternatively, reductive amination(s) ofintermediates of Formula XXIV with an aldehyde(s) also providespyrazoles of Formula I where n=0 and X is —NR⁵— as indicated below.Intermediates of Formula XXIV can also be elaborated by treatment with acyclic anhydride such as succinic or glutaric anhydride, to givepyrazoles of Formula I where n=0, X is —NR⁵—C(O)—, and the alkylfragment Y is substituted with Z=—C(O)OH. It is also possible to carryout further reactions on certain compounds of Formula I to produceadditional examples of compounds of Formula I. For example, reductiveamination (using a suitable aldehyde) of a compound of Formula I where Xis —NR⁵— and R⁵═H provides a compound of Formula I where X is —NR⁵— andR⁵ is not hydrogen. Also, reaction of a compound of Formula I where X is—NR⁵— and R⁵═H with a sulfamoyl chloride R⁷R⁸N—SO₂Cl provides a compoundof Formula I where X is —N(SO₂NR⁷R⁸)—.

Compounds of Formula I where n=1 and X is —NR⁵— or —NR⁵—C(O)— can beprepared as indicated below. In this case, a compound of Formula XXV inwhich the group A is substituted with a cyano functionality is reduced(for example, by the use of lithium aluminum hydride) to provide therelated aminomethylene-substituted compound of Formula I where n=0, X isa bond, Y is —CH₂— and Z is —NH₂. Then, in a similar manner to thatdescribed above, compounds of Formula I where n=1 and X is —NR⁵— or—NR⁵—C(O)— can be prepared by applying standard coupling reactionsand/or reductive amination reactions.

Compounds of Formula I where n=1 and X is —O— can be prepared asindicated in the scheme below. In this case, a compound of Formula XXVIin which the group A is substituted with an ester functionality isreduced (for example, by the use of lithium aluminum hydride) to providethe related hydroxymethylene-substituted compound of Formula I wheren=0, X is a bond, Y is —CH₂— and Z is —OH. Then, the hydroxyfunctionality can be derivatized, for example by conversion to thecorresponding methanesulfonate or 4-toluenesulfonate (a compound ofFormula XXVII) followed by reaction with Y—OH, to give compounds ofFormula I where n=1 and X is —O—.

The preparation of several additional examples of compounds of Formula Iare illustrated in the following scheme. The ester functionality in acompound of Formula XXVIII can be hydrolyzed under standard conditionsto form the compound of Formula I where n=0, X is a bond, Y is CH₂, andZ=C(O)OH. This compound of Formula I can be converted to various otherexamples of compounds of Formula I by reduction and amide-couplingreactions as indicated in the scheme. For example, an amide-couplingreaction with an amine R⁷R⁸NH gives a compound of Formula I where n=0, Xis a bond, Y is CH₂, and Z=—C(O)NR⁷R⁸, and a subsequent reductionreaction provides a compound of Formula I where n=0, X is a bond, Y isCH₂CH₂, and Z=—NR⁷R⁸.

Synthetic transformations that may be employed in the synthesis ofcompounds of Formula I and in the synthesis of intermediates involved inthe synthesis of compounds of Formula I are known by or accessible toone skilled in the art. Collections of synthetic transformations may befound in compilations, such as:

-   J. March. Advanced Organic Chemistry, 4th ed.; John Wiley: New York    (1992)-   R. C. Larock. Comprehensive Organic Transformations, 2nd ed.;    Wiley-VCH: New York (1999)-   F. A. Carey; R. J. Sundberg. Advanced Organic Chemistry, 2nd ed.;    Plenum Press: New York (1984)-   T. W. Greene; P. G. M. Wuts. Protective Groups in Organic Synthesis,    3rd ed.; John Wiley: New York (1999)-   L. S. Hegedus. Transition Metals in the Synthesis of Complex Organic    Molecules, 2nd ed.; University Science Books: Mill Valley, Calif.    (1994)-   L. A. Paquette, Ed. The Encyclopedia of Reagents for Organic    Synthesis; John Wiley: New York (1994)-   A. R. Katritzky; O. Meth-Cohn; C. W. Rees, Eds. Comprehensive    Organic Functional-   Group Transformations; Pergamon Press: Oxford, UK (1995)-   G. Wilkinson; F. G A. Stone; E. W. Abel, Eds. Comprehensive    Organometallic Chemistry; Pergamon Press: Oxford, UK (1982)-   B. M. Trost; I. Fleming. Comprehensive Organic Synthesis; Pergamon    Press: Oxford, UK (1991)-   A. R. Katritzky; C. W. Rees Eds. Comprehensive Heterocylic    Chemistry; Pergamon Press: Oxford, UK (1984)-   A. R. Katritzky; C. W. Rees; E. F. V. Scriven, Eds. Comprehensive    Heterocylic Chemistry II; Pergamon Press: Oxford, UK (1996)-   C. Hansch; P. G. Sammes; J. B. Taylor, Eds. Comprehensive Medicinal    Chemistry: Pergamon Press: Oxford, UK (1990).

In addition, recurring reviews of synthetic methodology and relatedtopics include Organic Reactions; John Wiley: New York; OrganicSyntheses; John Wiley: New York; Reagents for Organic Synthesis: JohnWiley: New York; The Total Synthesis of Natural Products; John Wiley:New York; The Organic Chemistry of Drug Synthesis; John Wiley New York;Annual Reports in Organic Synthesis; Academic Press: San Diego Calif.;and Methoden der Organischen Chemie (Houben-Weyl); Thieme: Stuttgart,Germany. Furthermore, databases of synthetic transformations includeChemical Abstracts, which may be searched using either CAS OnLine orSciFinder, Handbuch der Organischen Chemie (Beilstein), which may besearched using SpotFire, and REACCS.

Compositions of the Compounds of this Invention

This invention also relates to pharmaceutical compositions containingone or more compounds of the present invention. These compositions canbe utilized to achieve the desired pharmacological effect byadministration to a patient in need thereof. A patient, for the purposeof this invention, is a mammal, including a human, in need of treatmentfor the particular condition or disease. Therefore, the presentinvention includes pharmaceutical compositions that are comprised of apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of a compound, or salt thereof, of the present invention. Apharmaceutically acceptable carrier is preferably a carrier that isrelatively non-toxic and innocuous to a patient at concentrationsconsistent with effective activity of the active ingredient so that anyside effects ascribable to the carrier do not vitiate the beneficialeffects of the active ingredient. A pharmaceutically effective amount ofcompound is preferably that amount which produces a result or exerts aninfluence on the particular condition being treated. The compounds ofthe present invention can be administered withpharmaceutically-acceptable carriers well known in the art using anyeffective conventional dosage unit forms, including immediate, slow andtimed release preparations, orally, parenterally, topically, nasally,ophthalmically, optically, sublingually, rectally, vaginally, and thelike.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions, and may beprepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule that can be of the ordinary hard- or soft-shelled gelatin typecontaining, for example, surfactants, lubricants, and inert fillers suchas lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatin,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, coloring agents, and flavoring agents such as peppermint, oil ofwintergreen, or cherry flavoring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example those sweetening, flavoring and coloring agentsdescribed above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more coloring agents; one or more flavoringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavoring and coloring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in preferably a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile liquid or mixture ofliquids such as water, saline, aqueous dextrose and related sugarsolutions, an alcohol such as ethanol, isopropanol, or hexadecylalcohol, glycols such as propylene glycol or polyethylene glycol,glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, etherssuch as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acidester or, a fatty acid glyceride, or an acetylated fatty acid glyceride,with or without the addition of a pharmaceutically acceptable surfactantsuch as a soap or a detergent, suspending agent such as pectin,carbomers, methycellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agent and other pharmaceuticaladjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimize or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) preferably of from about 12 to about17. The quantity of surfactant in such formulation preferably rangesfrom about 5% to about 15% by weight. The surfactant can be a singlecomponent having the above HLB or can be a mixture of two or morecomponents having the desired HLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are, for example, cocoa butter and polyethyleneglycol.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No.5,023,252, issued Jun. 11, 1991, incorporated herein by reference). Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations that areknown in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques for,for example, administering a drug directly to the brain usually involveplacement of a drug delivery catheter into the patient's ventricularsystem to bypass the blood-brain barrier. One such implantable deliverysystem, used for the transport of agents to specific anatomical regionsof the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30,1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized. Such ingredients and procedures include those describedin the following references, each of which is incorporated herein byreference: Powell, M. F. et al, “Compendium of Excipients for ParenteralFormulations” PDA Journal of Pharmaceutical Science & Technology 1998,52(5), 238-311; Strickley, R. G “Parenteral Formulations of SmallMolecule Therapeutics Marketed in the United States (1999)-Part-1” PDAJournal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; andNema, S. et al, “Excipients and Their Use in Injectable Products” PDAJournal of Pharmaceutical Science & Technology 1997, 51 (4), 166-171.

Commonly used pharmaceutical ingredients that can be used as appropriateto formulate the composition for its intended route of administrationinclude:

acidifying agents (examples include but are not limited to acetic acid,citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalinizing agents (examples include but are not limited to ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine);

adsorbents (examples include but are not limited to powdered celluloseand activated charcoal);

aerosol propellants (examples include but are not limited to carbondioxide, CCl₂F₂, F₂ClC—CClF₂ and CClF₃)

air displacement agents (examples include but are not limited tonitrogen and argon);

antifungal preservatives (examples include but are not limited tobenzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben,sodium benzoate);

antimicrobial preservatives (examples include but are not limited tobenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate and thimerosal);

antioxidants (examples include but are not limited to ascorbic acid,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate,sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite);

binding materials (examples include but are not limited to blockpolymers, natural and synthetic rubber, polyacrylates, polyurethanes,silicones, polysiloxanes and styrene-butadiene copolymers);

buffering agents (examples include but are not limited to potassiummetaphosphate, dipotassium phosphate, sodium acetate, sodium citrateanhydrous and sodium citrate dihydrate)

carrying agents (examples include but are not limited to acacia syrup,aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orangesyrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,bacteriostatic sodium chloride injection and bacteriostatic water forinjection)

chelating agents (examples include but are not limited to edetatedisodium and edetic acid)

colorants (examples include but are not limited to FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&COrange No. 5, D&C Red No. 8, caramel and ferric oxide red);

clarifying agents (examples include but are not limited to bentonite);

emulsifying agents (examples include but are not limited to acacia,cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitanmonooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include but are not limited to gelatinand cellulose acetate phthalate)

flavorants (examples include but are not limited to anise oil, cinnamonoil, cocoa, menthol, orange oil, peppermint oil and vanillin);

humectants (examples include but are not limited to glycerol, propyleneglycol and sorbitol);

levigating agents (examples include but are not limited to mineral oiland glycerin);

oils (examples include but are not limited to arachis oil, mineral oil,olive oil, peanut oil, sesame oil and vegetable oil);

ointment bases (examples include but are not limited to lanolin,hydrophilic ointment, polyethylene glycol ointment, petrolatum,hydrophilic petrolatum, white ointment, yellow ointment, and rose waterointment);

penetration enhancers (transdermal delivery) (examples include but arenot limited to monohydroxy or polyhydroxy alcohols, mono- or polyvalentalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas)

plasticizers (examples include but are not limited to diethyl phthalateand glycerol);

solvents (examples include but are not limited to ethanol, corn oil,cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanutoil, purified water, water for injection, sterile water for injectionand sterile water for irrigation);

stiffening agents (examples include but are not limited to cetylalcohol, cetyl esters wax, microcrystalline wax, paraffin, stearylalcohol, white wax and yellow wax);

suppository bases (examples include but are not limited to cocoa butterand polyethylene glycols (mixtures));

surfactants (examples include but are not limited to benzalkoniumchloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium laurylsulfate and sorbitan mono-palmitate);

suspending agents (examples include but are not limited to agar,bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,kaolin, methylcellulose, tragacanth and veegum);

sweetening agents (examples include but are not limited to aspartame,dextrose, glycerol, mannitol, propylene glycol, saccharin sodium,sorbitol and sucrose);

tablet anti-adherents (examples include but are not limited to magnesiumstearate and talc);

tablet binders (examples include but are not limited to acacia, alginicacid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose,gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);

tablet and capsule diluents (examples include but are not limited todibasic calcium phosphate, kaolin, lactose, mannitol, microcrystallinecellulose, powdered cellulose, precipitated calcium carbonate, sodiumcarbonate, sodium phosphate, sorbitol and starch);

tablet coating agents (examples include but are not limited to liquidglucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetatephthalate and shellac);

tablet direct compression excipients (examples include but are notlimited to dibasic calcium phosphate);

tablet disintegrants (examples include but are not limited to alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose,polacrillin potassium, cross-linked polyvinylpyrrolidone, sodiumalginate, sodium starch glycollate and starch);

tablet glidants (examples include but are not limited to colloidalsilica, corn starch and talc);

tablet lubricants (examples include but are not limited to calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate);

tablet/capsule opaquants (examples include but are not limited totitanium dioxide);

tablet polishing agents (examples include but are not limited to carnubawax and white wax);

thickening agents (examples include but are not limited to beeswax,cetyl alcohol and paraffin);

tonicity agents (examples include but are not limited to dextrose andsodium chloride);

viscosity increasing agents (examples include but are not limited toalginic acid, bentonite, carbomers, carboxymethylcellulose sodium,methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth);and

wetting agents (examples include but are not limited toheptadecaethylene oxycetanol, lecithins, sorbitol monooleate,polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can beillustrated as follows:

Sterile IV Solution: A 5 mg/mL solution of the desired compound of thisinvention can be made using sterile, injectable water, and the pH isadjusted if necessary. The solution is diluted for administration to 1-2mg/mL with sterile 5% dextrose and is administered as an IV infusionover about 60 minutes.Lyophilized powder for IV administration: A sterile preparation can beprepared with (i) 100-1000 mg of the desired compound of this inventionas a lypholized powder, (ii) 32-327 mg/mL sodium citrate, and (iii)300-3000 mg Dextran 40. The formulation is reconstituted with sterile,injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL,which is further diluted with saline or dextrose 5% to 0.2-0.4 mg/mL,and is administered either IV bolus or by IV infusion over 15-60minutes.Intramuscular suspension: The following solution or suspension can beprepared, for intramuscular injection:

50 mg/mL of the desired, water-insoluble compound of this invention

5 mg/mL sodium carboxymethylcellulose

4 mg/mL TWEEN 80

9 mg/mL sodium chloride

9 mg/mL benzyl alcohol

Hard Shell Capsules: A large number of unit capsules are prepared byfilling standard two-piece hard galantine capsules each with 100 mg ofpowdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6mg of magnesium stearate.Soft Gelatin Capsules: A mixture of active ingredient in a digestibleoil such as soybean oil, cottonseed oil or olive oil is prepared andinjected by means of a positive displacement pump into molten gelatin toform soft gelatin capsules containing 100 mg of the active ingredient.The capsules are washed and dried. The active ingredient can bedissolved in a mixture of polyethylene glycol, glycerin and sorbitol toprepare a water miscible medicine mix.Tablets: A large number of tablets are prepared by conventionalprocedures so that the dosage unit is 100 mg of active ingredient, 0.2mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose.Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.Immediate Release Tablets/Capsules: These are solid oral dosage formsmade by conventional and novel processes. These units are taken orallywithout water for immediate dissolution and delivery of the medication.The active ingredient is mixed in a liquid containing ingredient such assugar, gelatin, pectin and sweeteners. These liquids are solidified intosolid tablets or caplets by freeze drying and solid state extractiontechniques. The drug compounds may be compressed with viscoelastic andthermoelastic sugars and polymers or effervescent components to produceporous matrices intended for immediate release, without the need ofwater.

Method of Treating Hyper-Proliferative Disorders

The present invention relates to a method for using the compoundsdescribed above (Compounds of Formula I, salts thereof, stereoisomersthereof, esters thereof, etc.) and compositions thereof, to treatmammalian hyper-proliferative disorders. This method comprisesadministering to a mammal in need thereof, including a human, an amountof a compound of this invention, (Compounds of Formula I or apharmaceutically acceptable salt, isomer, or ester thereof; etc.) whichis effective to treat the disorder. Hyper-proliferative disordersinclude but are not limited, e.g., psoriasis, keloids, and otherhyperplasias affecting the skin, benign prostate hyperplasia (BPH),solid tumors, such as cancers of the breast, respiratory tract, brain,reproductive organs, digestive tract, urinary tract, eye, liver, skin,head and neck, thyroid, parathyroid and their distant metastases. Thosedisorders also include lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumor.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumors of the female reproductive organsinclude, but are not limited to endometrial, cervical, ovarian, vaginal,and vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, and urethral cancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited tolaryngeal/hypopharyngeal/nasopharyngeal/oropharyngeal cancer, and lipand oral cavity cancer.

Lymphomas include, but are not limited to AIDS-related lymphoma,non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease,and iymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

Inappropriate and ectopic expression of angiogenesis can be deleteriousto an organism. A number of pathological conditions are associated withthe growth of extraneous blood vessels. These include, e.g., diabeticretinopathy, ischemic retinal-vein occlusion, and retinopathy ofprematurity (Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer etal. Lab. Invest. 1995, 72, 638), age-related macular degeneration (AMD;see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855),neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma,inflammation, rheumatoid arthritis (RA), restenosis, in-stentrestenosis, vascular graft restenosis, etc. In addition, the increasedblood supply associated with cancerous and neoplastic tissue, encouragesgrowth, leading to rapid tumor enlargement and metastasis. Moreover, thegrowth of new blood and lymph vessels in a tumor provides an escaperoute for renegade cells, encouraging metastasis and the consequencespread of the cancer. Thus, compounds of the present invention can beutilized to treat and/or prevent any of the aforementioned angiogenesisdisorders.

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of hyper-proliferative disorders, by standardtoxicity tests and by standard pharmacological assays for thedetermination of treatment of the conditions identified above inmammals, and by comparison of these results with the results of knownmedicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of each desired indication. The amount of the activeingredient to be administered in the treatment of one of theseconditions can vary widely according to such considerations as theparticular compound and dosage unit employed, the mode ofadministration, the period of treatment, the age and sex of the patienttreated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. It should be noted that the choice of dosing schedulesis particularly important to maximize the efficacy and safety of drugsfor the treatment of proliferative disorders such as cancer. Clinicallyuseful dosing schedules will range from three times a day dosing to onceevery four weeks dosing. In addition, “drug holidays” in which a patientis not dosed with a drug for a certain period of time, may be beneficialto the overall balance between pharmacological effect and tolerability.A unit dosage may contain from about 0.5 mg to about 1500 mg of activeingredient, and can be administered one or more times per day or lessthan once a day. The average daily dosage for administration byinjection, including intravenous, intramuscular, subcutaneous andparenteral injections, and use of infusion techniques will preferably befrom 0.01 to 200 mg/kg of total body weight. The average daily rectaldosage regimen will preferably be from 0.01 to 200 mg/kg of total bodyweight. The average daily vaginal dosage regimen will preferably be from0.01 to 200 mg/kg of total body weight. The average daily topical dosageregimen will preferably be from 0.1 to 200 mg administered between oneto four times daily. The transdermal concentration will preferably bethat required to maintain a daily dose of from 0.01 to 200 mg/kg. Theaverage daily inhalation dosage regimen will preferably be from 0.01 to100 mg/kg of total body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

The compounds of this invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. For example, the compounds of this invention can becombined with known anti-hyper-proliferative or other indication agents,and the like, as well as with admixtures and combinations thereof.

The additional pharmaceutical agent can be aldesleukin, alendronic acid,alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine,aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole,anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine,azathioprine, BCG or tice BCG, bestatin, betamethasone acetate,betamethasone sodium phosphate, bexarotene, bleomycin sulfate,broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine,carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil,cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadronphosphate, delestrogen, denileukin diftitox, depo-medrol, deslorelin,dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine,doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend,epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, estrace,estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyol,etidronic acid, etopophos, etoposide, fadrozole, farston, filgrastim,finasteride, fligrastim, floxuridine, fluconazole, fludarabine,5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU),fluoxymesterone, flutamide, formestane, fosteabine, fotemustine,fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel,goserelin, granisetron HCl, histrelin, hycamtin, hydrocortone,eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan,idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferonalfa-2A, interferon alfa-2B, interferon alfa-n1, interferon alfa-n3,interferon beta, interferon gamma-1a, interleukin-2, intron A, iressa,irinotecan, kytril, lentinan sulphate, letrozole, leucovorin,leuprolide, leuprolide acetate, levamisole, levofolinic acid calciumsalt, levothroid, levoxyl, lomustine, lonidamine, marinol,mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrolacetate, melphalan, menest, 6-mercaptopurine, Mesna, methotrexate,metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone,Modrenal, Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide,nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCl, orapred,oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin,picibanil, pilocarpine HCl, pirarubicin, plicamycin, porfimer sodium,prednimustine, prednisolone, prednisone, premarin, procarbazine,procrit, raltitrexed, rebif, rhenium-186 etidronate, rituximab,roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine,sizofuran, sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy,streptozocin, strontium-89 chloride, synthroid, tamoxifen, tamsulosin,tasonermin, tastolactone, taxotere, teceleukin, temozolomide,teniposide, testosterone propionate, testred, thioguanine, thiotepa,thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab,trastuzumab, treosulfan, tretinoin, trexall, trimethylmelamine,trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine,valrubicin, vesnarinone, vinblastine, vincristine, vindesine,vinorelbine, virulizin, zinecard, zinostatin stimalamer, zofran,ABI-007, acolbifene, actimmune, affinitak, aminopterin, arzoxifene,asoprisnil, atamestane, atrasentan, BAY 43-9006, avastin, CCI-779,CDC-501, celebrex, cetuximab, crisnatol, cyproterone acetate,decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin,eflornithine, exatecan, fenretinide, histamine dihydrochloride,histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid,interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin,L-651582, lanreotide, lasofoxifene, libra, lonafarnib, miproxifene,minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin,neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxelpolyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, R-1549,raloxifene, ranpirnase, 13-cis-retinoic acid, satraplatin, seocalcitol,T-138067, tarceva, taxoprexin, thymosin alpha 1, tiazofurine,tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar,vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acidor combinations thereof.

Optional anti-hyper-proliferative agents which can be added to thecomposition include but are not limited to compounds listed on thecancer chemotherapy drug regimens in the 11^(th) Edition of the MerckIndex, (1996), which is hereby incorporated by reference, such asasparaginase, bleomycin, carboplatin, carmustine, chlorambucil,cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine,dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin,etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide,irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine,mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone,prednisone, procarbazine, raloxifen, streptozocin, tamoxifen,thioguanine, topotecan, vinblastine, vincristine, and vindesine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to thosecompounds acknowledged to be used in the treatment of neoplasticdiseases in Goodman and Gilman's The Pharmacological Basis ofTherapeutics (Ninth Edition), editor Molinoff et al., publ. byMcGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated byreference, such as aminoglutethimide, L-asparaginase, azathioprine,5-azacytidine cladribine, busulfan, diethylstilbestrol,2′,2′-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine,ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridinemonophosphate, fludarabine phosphate, fluoxymesterone, flutamide,hydroxyprogesterone caproate, idarubicin, interferon,medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane,paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA),plicamycin, semustine, teniposide, testosterone propionate, thiotepa,trimethylmelamine, uridine, and vinorelbine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to otheranti-cancer agents such as epothilone and its derivatives, irinotecan,raloxifen and topotecan.

Generally, the use of cytotoxic and/or cytostatic agents in combinationwith a compound or composition of the present invention will serve to:

(1) yield better efficacy in reducing the growth of a tumor or eveneliminate the tumor as compared to administration of either agent alone,(2) provide for the administration of lesser amounts of the administeredchemo-therapeutic agents,(3) provide for a chemotherapeutic treatment that is well tolerated inthe patient with fewer deleterious pharmacological complications thanobserved with single agent chemotherapies and certain other combinedtherapies,(4) provide for treating a broader spectrum of different cancer types inmammals, especially humans,(5) provide for a higher response rate among treated patients,(6) provide for a longer survival time among treated patients comparedto standard chemotherapy treatments,(7) provide a longer time for tumor progression, and/or(8) yield efficacy and tolerability results at least as good as those ofthe agents used alone, compared to known instances where other canceragent combinations produce antagonistic effects.

EXAMPLES Abbreviations

aq aqueousmin minute(s)h hour(s)

ADDP 1,1′-(Azodicarbonyl)dipiperidine

DMA N,N-Dimethyl acetamideDMF N,N-Dimethyl formamide

DCM Dichloromethane DCE 1,2-Dichloroethane

EtOAc Ethyl acetate

EtOH Ethanol MeOH Methanol THF Tetrahydrofuran

DMSO Dimethyl sulphoxideMTBE Methyl tert-butyl etherHPLC High pressure liquid chromatographyMPLC Medium pressure liquid chromatographyLC-MS Liquid chromatography-coupled mass spectroscopyRT Retention timeNMR Nuclear resonance spectroscopyTLC Thin layer chromatography

ES Electrospray CDT 1,1′-Carbonylditriazole CDI 1,1′-CarbonyldiimidazoleHOBT 1-Hydroxybenzotriazole

EDCI 1-[3-(Dimethylamino) propyl]-3-ethylcarbodiimide hydrochlorideTMSCl Trimethylsilyl chloride

Et₃N Triethylamine

NH₄Cl Ammonium chlorideNa₂SO₄ Sodium sulfateMgSO₄ Magnesium sulfateHEPES N-(2-hydroxyethyl)-piperazine-N′-(2-ethane sulfonic acid)

The percentage yields reported in the following examples are based onthe starting component that was used in the lowest molar-amount.

LC-MS: HPLC-electrospray mass spectra (HPLC ES-MS) were obtained using aGilson HPLC system equipped with two Gilson 306 pumps, a Gilson 215Autosampler, a Gilson diode array detector, a YMC Pro C-18 column (2×23mm, 120 A), and a Micromass LCZ single quadrupole mass spectrometer withz-spray electrospray ionization. Spectra were scanned from 120-1000 amuover 2 seconds. ELSD (Evaporative Light Scattering Detector) data wasalso acquired as an analog channel. Gradient elution was used withBuffer A as 2% acetonitrile in water with 0.02% TFA and Buffer B as 2%water in acetonitrile with 0.02% TFA at 1.5 mL/min. Samples were elutedas follows: 90% A for 0.5 minutes ramped to 95% B over 3.5 minutes andheld at 95% B for 0.5 minutes, and then the column was brought back toinitial conditions over 0.1 minutes. Total run time was 4.8 minutes.Preparative HPLC: Preparative HPLC was carried out in reversed phasemode, eluting with aqueous acetonitrile containing 0.5% TFA, typicallyusing a Gilson HPLC system equipped with two Gilson 322 pumps, a Gilson215 Autosampler, a Gilson diode array detector, and a YMC Pro C-18column (20×150 mm, 120 A). Gradient elution was used with Buffer A aswater with 0.1% TFA and Buffer B as acetonitrile with 0.1% TFA. Samplewas dissolved in MeOH or MeOH/DMSO with concentration about 50 mg/mL.Injection volume was about 2-3 mL/injection. Sample was typically elutedas follows: 10-90% B over 15 minutes with flow rate of 25 mL/min, hold 2minutes, back to 10% B. The desired fraction(s) were collected by UVmonitoring at 254 or 220 nm and evaporated by using a GeneVaccentrifugal vacuum instrument.Preparative MPLC: Preparative medium pressure liquid chromatography(MPLC) was carried out by standard silica gel “flash chromatography”techniques (e.g., Still, W. C. et al. J. Org. Chem. 1978, 43, 2923-5),or by using silica gel cartridges and devices such as the Biotage Flashsystems. A variety of eluting solvents were used, as described in theexperimental protocols.

Preparation of Intermediates Preparation of5-tert-butyl-2-(4-nitro-Phenyl)-2H-pyrazol-3-Ylamine

To a solution of 4,4-dimethyl-3-oxopentanenitrile (20.4 g, 163 mmol) and4-nitrophenylhydrazine (25.0 g, 163 mmol) in anhydrous EtOH (300 mL) wasadded acetic acid (3.4 mL, 60 mL) dropwise. The reaction was stirred atreflux under N₂ for 18 h. The reaction mixture was cooled to roomtemperature and concentrated at reduced pressure. The residue waspartitioned between EtOAc (500 mL) and aqueous saturated NaHCO₃ solution(300 mL). The organic layer was washed with water and brine, dried overNa₂SO₄, and concentrated at reduced pressure. The crude residue waspurified by MPLC (eluting with 80:20 hexanes/EtOAc) to give 36.0 g (85%)of the desired product. ¹H-NMR (DMSO-d₆) δ 8.28 (d, J=6.9 Hz, 2H), 7.93(d, J=6.9 Hz, 2H), 5.55 (s, 2H), 5.46 (s, 1H), 1.20 (s, 9H); MS LC-MS[M+H]⁺=261, RT=2.74 min.

Preparation of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)-benzonitrile

The title compound was prepared (85% yield) in the same manner asdescribed for 5-tert-butyl-2-(4-nitro-phenyl)-2H-pyrazol-3-ylamine,replacing 4-nitrophenylhydrazine with 4-cyanophenylhydrazine. MS LC-MS[M+H]⁺=241, RT=2.39 min.

Preparation of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)benzoic acid

A mixture of 4,4-dimethyl-3-oxo-pentanenitrile (4.52 g, 36.15 mmol),4-hydrazinobenzoic acid (5.00 g, 32.86 mmol), and acetic acid (2 mL) inEtOH/THF (1:1) was refluxed for 16 h. After cooling, the solvent wasconcentrated at reduced pressure, and the crude was re-dissolved inEtOAc. The organic layer was washed with aqueous saturated Na₂CO₃solution and brine, dried over MgSO₄, filtered, and concentrated to halfits volume. The resulting residue was filtered, and the solids werewashed with cold EtOAc and dried under high vacuum to afford the titlecompound as a white solid (8.4 g, 99%). ¹H-NMR (DMSO-d₆) δ 12.91 (s,1H), 7.99 (d, J=6.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H), 5.42 (s, 1H), 5.39(s, 2H), 1.21 (s, 9H); MS LC-MS [M+H]⁺=260, RT=1.83 min.

Preparation of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)benzoic acid methylester

To anhydrous methanol at 0° C. was added dropwise TMSCl (12.57 g, 115.0mmol). After 10 minutes a solution of4-(5-amino-3-tert-butyl-pyrazol-1-ylbenzoic acid (3.00 g, 11.57 mmol) inanhydrous methanol was added dropwise, and the reaction mixture wasstirred at 80° C. for 16 h. The volatile solvent was removed and thecrude was partitioned between EtOAc and aqueous saturated Na₂CO₃solution. The organic layer was washed with water and brine, dried overMgSO₄, and concentrated at reduced pressure. The resultant solid wastriturated from hexane, filtered, and dried under high vacuum to afford2.23 g (71%) of the title compound as a white solid. ¹H-NMR (DMSO-d₆) δ8.07 (d, J=9.0 Hz, 2H), 7.87 (d, J=12.0 Hz, 2H), 5.57 (s, 1H), 4.97 (s,2H), 3.90 (s, 3H), 1.26 (s, 9H); MS LC-MS [M+H]⁺=274, RT=2.74 min.

Preparation of4-(3-tert-butyl-5-phenoxycarbonylamino-pyrazol-1-yl)-benzoic acid methylester

To a solution of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)-benzoic acidmethyl ester (5.3 g, 19.4 mmol) in anhydrous THF (200 mL) was slowlyadded phenyl chloroformate (6.81 mL, 54.3 mmol), followed by sodiumcarbonate (2.1 g, 19.4 mmol). The mixture was stirred at roomtemperature overnight. Ethyl acetate (500 mL) was added, followed bysaturated sodium carbonate (300 mL). The organic layer was washed withsaturated sodium carbonate (3×) and brine (1×), dried over MgSO₄, andconcentrated at reduced pressure. The residue was washed with ether togive 4.3 g (56%) of the desired product. ¹H-NMR (DMSO-d₆) δ 10.19 (s,1H), 8.10 (d, J=9.0 Hz, 2H), 7.73 (d, J=9.0 Hz, 2H), 7.38-7.11 (m, 5H),6.41 (s, 1H), 3.87 (s, 3H), 1.27 (s, 1H); MS LC-MS [M+H]⁺=394.1, RT=3.53min.

Preparation of 5-tert-butyl-2-(4-methoxyphenyl)-2H-pyrazol-3-ylamine

The title compound was prepared in the same manner as described for4-(5-amino-3-tert-butyl-pyrazol-1-yl)benzoic acid, replacing4-hydrazinobenzoic acid with 4-methoxyphenylhydrazine. ¹H-NMR (DMSO-d₆)δ 7.40 (d, J=5.1 Hz, 2H), 6.98 (d, J=4.8 Hz, 2H), 5.32 (s, 1H), 5.05 (s,2H), 3.77 (s, 3H), 1.20 (s, 9H); MS LC-MS [M+H]⁺=246, RT=1.76 min.

Preparation of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)phenol

To a stirred solution of5-tert-butyl-2-(4-methoxyphenyl)-2H-pyrazol-3-ylamine (5.3 g, 21.6 mmol)in anhydrous DCM (43.2 mL) was added aluminum trichloride (14.4 g, 108.0mmol, 5.0 eq) proportion wise, and the reaction was stirred at refluxfor 18 h. The cooled reaction was poured into ethyl acetate, and theorganic layer was washed with water and brine, dried over Na₂SO₄,filtered, and concentrated at reduced pressure. Crystallization fromDCM/ether afforded the title compound (2.71 g, 54%) as a white solid.¹H-NMR (DMSO-d₆) δ 9.47 (s, 1H), 7.21 (d, J=9.0 Hz, 2H), 6.75 (d, J=8.7Hz, 2H), 5.25 (s, 1H), 4.91 (broad s, 2H), 1.13 (s, 9H); MS LC-MS[M+H]⁺=232, RT=1.13 min; TLC (35% EtOAc/hex), R_(f)=0.13.

Preparation of5-tert-butyl-2-[4-(2-methoxyethoxy)phenyl]-2H-pyrazol-3-ylamine

A mixture of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)phenol (500 mg, 2.16mmol), 2-methoxyethanol (164.5 mg, 2.16 mmol), ADDP (818.2 mg, 3.24mmol, 1.5 eq), and triphenylphosphine (850.5 mg, 3.24 mmol, 1.5 eq) inanhydrous THF was stirred at ambient temperature under nitrogen for 18h. The reaction mixture was poured into EtOAc, and the organic layer waswashed with water and brine, dried over Na₂SO₄, filtered, andconcentrated at reduced pressure. Purification by MPLC (eluting with 25%EtOAc/hexane) gave an oil which solidified upon standing, 507 mg (81%).¹H-NMR (DMSO-d₆) δ 7.39 (dd, J=6.6, 2.4 Hz, 2H), 6.97 (dd, J=6.9, 2.7Hz, 2H), 5.30 (s, 1H), 5.02 (broad s, 2H), 4.09 to 4.06 (m, 2H), 3.65 to3.62 (m, 2H), 3.28 (s, 3H), 1.16 (s, 9H); MS LC-MS [M+H]⁺=290, RT=1.35min.

Preparation of5-tert-butyl-2-[4-(2-diethylaminoethoxy-phenyl]-2H-pyrazol-3-ylamine

To a solution of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenol (300 mg,1.30 mmol) in anhydrous 2-butanone (5.2 mL) was added2-(diethylamino)ethyl chloride hydrochloride (245.5 mg, 1.43 mmol, 1.1eq), potassium carbonate (448.2 mg, 3.24 mmol, 2.5 eq), and sodiumiodide (19.4 mg, 0.13 mmol, 0.1 eq), and the reaction mixture wasstirred at 60° C. for 3 days. The cooled reaction was poured into EtOAc,and the organic layer was washed with water and brine, dried overNa₂SO₄, filtered, and concentrated at reduced pressure. Purification byMPLC (1:4 MeOH/EtOAc) afforded the title compound (133 mg, 31%) as asyrup. ¹H-NMR (CD₃OD) δ 7.35 (d, J=9.3 Hz, 2H), 7.00 (d, J=9.0 Hz, 2H),5.82 (s, 1H), 4.14 (t, J=5.4 Hz, 2H), 2.96 (t, J=5.7 Hz, 2H), 2.72 (q,J=7.2 Hz, 4H), 1.33 (s, 9H), 1.12 (t, J=7.2 Hz, 6H); MS LC-MS[M+H]⁺=331, RT=0.33 min.

Preparation of4-{2-[4-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenol (550 mg,2.4 mmol) and 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acidtert-butyl ester (505 mg, 2.18 mmol) in 50 mL THF was added ADDP (825mg, 3.28 mmol) and triphenylphosphine (858 mg, 3.28 mmol). The reactionmixture was stirred at room temperature under nitrogen overnight. Thesolid was removed by filtration, the filtrate was concentrated and theresidue was purified by MPLC (80:20 hexane/EtOAc) to give the desiredproduct4-{2-[4-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester 800 mg (83%). ¹H-NMR (DMSO-d₆) δ 7.40 (d, 2H),7.00 (d, 2H), 5.35 (s, 1H), 5.0 (s, 2H), 4.0 (m, 2H), 3.90 (m, 2H),1.70-1.60 (m, 6H), 1.40 (s, 9H), 1.20 (s, 9H), 1.05 (m, 1H); MS LC-MS[M+H]⁺=443.3, RT=3.10 min.

Preparation of 5-tert-butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-ylaminehydrochloride

To a solution of 4,4-dimethyl-3-oxo-pentanenitrile (5.0 g, 40 mmol) and3-methoxy-phenylhydrazine hydrochloride (7.0 g, 40 mmol) in anhydrousethanol (200 mL) was added acetic acid (1.2 mL). The reaction mixturewas heated at reflux overnight, then cooled to room temperature andconcentrated at reduced pressure. The residue was combined with ethylacetate (200 mL), and washed with saturated aq NaHCO₃, water, and brine.The solution was dried over Na₂SO₄, evaporated at reduced pressure andthe solid residue was re-dissolved in ethanol (100 mL). A solution of 2MHCl in ether was added and the mixture was stirred for 30 min. Thesolvent was removed at reduced pressure, the solid residue wastriturated and washed with hexane (50 mL) and then dried in a vacuumoven overnight to give the product5-tert-butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-ylamine hydrochloride(5.46 g, 56%) as an off-white solid. ¹H-NMR (DMSO-d₆) δ 7.50 (t, 1H),7.10 (m, 3H), 5.60 (s, 1H), 3.80 (s, 3H), 1.30 (s, 9H); MS LC-MS[M+H]⁺=246.2, RT=1.90 min.

Preparation of 3-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenol

In a 500 mL round bottom flask was added5-tert-butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-ylamine hydrochloride(8.42 g, 30 mmol) and pyridinium hydrochloride (13.8 g, 120 mmol). Thereaction mixture was heated neat at 195° C. with stirring for 3 h. Themixture was cooled to room temperature, water (300 mL) and EtOAc (300mL) were added, and then the organic phase was washed with saturated aqNaHCO₃ and brine, dried (Na₂SO₄) and concentrated at reduced pressure.The residue was purified by MPLC (80:20 hexane/EtOAc) to give theproduct 3-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenol (1.3 g, 19%).¹H-NMR (DMSO-d₆) δ 7.20 (t, 1H), 7.00 (m, 2H), 6.50 (d, 1H), 5.30 (s,1H), 5.10 (bs, 2H), 1.30 (s, 9H); MS LC-MS [M+H]⁺=232.2, RT=0.57 min.

Preparation of3-[3-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenoxy]-propan-1-ol

A mixture of 3-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenol (400 mg, 1.73mmol), 3-chloropropanol (326 mg, 3.46 mmol), potassium carbonate (596mg, 4.32 mmol) and sodium iodide (77 mg, 0.52 mmol) were combined inn-butanol (6 mL). The reaction mixture was heated at 60° C. for 4 days.The mixture was cooled to room temperature, water (100 mL) and EtOAc(100 mL) were added, and then the organic phase was washed with waterand brine, dried (Na₂SO₄), and concentrated at reduced pressure. Theresidue was purified by MPLC (80:20 hexane/EtOAc) to give the product3-[3-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenoxy]-propan-1-ol (400 mg,80%). ¹H-NMR (DMSO-d₆) δ 7.30 (t, 1H), 7.10 (m, 2H), 6.80 (d, 1H), 5.30(s, 1H), 5.10 (bs, 2H), 4.0 (t, 2H), 3.60 (t, 3H), 1.80 (m, 2H), 1.30(s, 9H); MS LC-MS [M+H]⁺=290.3, RT=1.05 min.

Preparation of 4-bromo-2-methyl-N-(2-morpholin-4-yl-ethyl)benzenesulfonamide

A mixture of 4-bromo-2-methylbenzene sulfonyl chloride (700 mg, 2.6mmol), 4-(2-aminoethyl)morpholine (372 mg, 2.86 mmol, 1.1 eq), andN,N-diisopropylethylamine (1.0 mL, 5.71 mmol, 2.2 eq) in anhydroustetrahydrofuran (13 mL, 0.2 M) was stirred at 40° C. under nitrogen for18 h. Solvent was removed at reduced pressure and the residue waspartitioned between EtOAc and water. The organic phase was washed withwater and brine, dried over Na₂SO₄, and concentrated at reducedpressure. The residue was purified by MPLC (eluting with 50% to 75%EtOAc/hexane) to give 939 mg (99%) of the desired product as a whitesolid. ¹H-NMR (DMSO-d₆) δ 7.73 (d, J=8.4 Hz, 1H), 7.68 (broad s, 1H),7.65 (dd, J=2.1, 0.6 Hz, 1H), 7.55 (ddd, J=7.3, 2.1, 0.6 Hz, 1H), 3.41(t, J=4.5 Hz, 4H), 2.88 (t, J=6.3 Hz, 2H), 2.56 (s, 3H), 2.19 (t_(r)=6.6Hz, 2H), 2.16 to 2.12 (m, 4H); MS LC-MS [M+H]⁺=363 & 365, RT=1.90 min.

Preparation of4-bromo-N-(2-morpholin-4-yl-ethyl)-2-trifluoromethoxy-benzenesulfonamide

The title compound was prepared in the same manner as described for4-bromo-2-methyl-N-(2-morpholin-4-yl-ethyl)benzene sulfonamide,replacing 4-bromo-2-methyl-benzene sulfonyl chloride with4-bromo-2-trifluoromethoxybenzene sulfonyl chloride. ¹H-NMR (DMSO-d₆) δ7.88 to 7.77 (m, 4H), 3.43 (t, J=4.2 Hz, 4H), 2.99 to 2.97 (broad s,2H), 2.29 to 2.20 (m, 6H); MS LC-MS [M+H]⁺=433 & 435, RT=2.03 min.

Preparation of 4-bromo-N-(2-morpholin-4-yl-ethyl)benzene sulfonamide

The title compound was prepared in the same manner as described for4-bromo-2-methyl-N-(2-morpholin-4-yl-ethyl)benzene sulfonamide,replacing 4-bromo-2-methyl-benzene sulfonyl chloride with 4-bromobenzenesulfonyl chloride. ¹H-NMR (DMSO-d₆) δ 7.81 to 7.68 (m, 4H), 7.66 (broads, 1H), 3.46 (t, J=4.8 Hz, 4H), 2.85 (t, J=6.6 Hz, 2H), 2.28 to 2.21 (m,6H); MS LC-MS [M+H]⁺=349 & 351, RT=1.34 min.

Preparation of 3-bromo-N-(2-methoxyethylbenzene sulfonamide

To a solution of 3-bromobenzenesulfonyl chloride (1.00 g, 3.72 mmol) inacetone (10 mL) was added 2-methoxyethylamine (0.97 mL, 11.15 mmol, 3.0eq) and potassium carbonate (2.57 g, 18.6 mmol, 5.0 eq), and thereaction was stirred at 40° C. for 5 h. The mixture was cooled to roomtemperature and then partitioned between EtOAc and water, and theorganic phase was washed with brine, dried over MgSO₄, and concentratedat reduced pressure. The residue was purified by MPLC (20% to 25%EtOAc/hexane) to give 1.05 g (96%) of the desired product as an oil. TLC[30% EtOAc/hexane], Rf=0.33.

Preparation of4-(5-amino-3-tert-butyl-pyrazol-1-yl)-2-methyl-N-(2-morpholin-4-yl-ethyl)-benzenesulfonamide Step 1: Preparation of4-(N′-benzhydrylidene-hydrazino)-2-methyl-N-(2-morpholin-4-yl-ethyl)-benzenesulfonamide

To a degassed solution of4-bromo-2-methyl-N-(2-morpholin-4-yl-ethyl)benzene-sulfonamide (939 mg,2.58 mmol), benzophenone hydrazone (558 mg, 2.84 mmol, 1.1 eq), and9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (75 mg, 0.13 mmol, 0.05eq) in anhydrous toluene (13 mL, 0.2M) was added sodium tert-butoxide(596 mg, 6.20 mmol, 2.4 eq) followed by palladium(II) acetate (29 mg,0.13 mmol, 0.05 eq), and the reaction mixture was stirred at 85° C.under nitrogen for 17 h. The reaction mixture was cooled to roomtemperature and was partitioned between EtOAc and water. The organiclayer was washed with water and brine, dried over Na₂SO₄, andconcentrated at reduced pressure. Purification by MPLC (75%EtOAc/hexane) afforded the title compound (1.00 g, 80%) as a whitesolid. ¹H-NMR (DMSO-d₆) δ 9.25 (s, 1H), 7.64 to 7.52 (m, 4H), 7.44 to7.41 (m, 2H), 7.35 to 7.26 (m, 5H), 7.16 to 7.13 (m, 3H), 3.45 (t, J=4.8Hz, 4H), 2.79 (q, J=6.3 Hz, 2H), 2.47 (s, 3H), 2.21 to 2.15 (m, 6H); MSLC-MS [M+H]⁺=479, RT=3.15 min.

Step 2: Preparation of4-(5-amino-3-tert-butyl-pyrazol-1-yl)-2-methyl-N-(2-morpholin-4-yl-ethyl)benzenesulfonamide

To a solution of4-(N′-benzhydrylidene-hydrazino)-2-methyl-N-(2-morpholin-4-yl-ethyl)-benzenesulfonamide (1.00 g, 2.09 mmol) and 4,4-dimethyl-3-oxopentanenitrile(392 mg, 3.13 mmol, 1.5 eq) in anhydrous ethanol (10.5 mL, 0.2 M) wasadded p-toluenebenzene sulfonic acid (402 mg, 4.18 mmol, 2.0 eq), andthe reaction mixture was stirred at reflux under nitrogen. After 18 h,concentrated HCl (2 mL) was added and the reaction mixture was stirredat reflux under nitrogen for an additional 4 h. The reaction mixture wascooled to room temperature and concentrated at reduced pressure. Theresidue was partitioned between EtOAc (500 mL) and aqueous saturatedNaHCO₃ solution (300 mL). The organic layer was washed with water andbrine, dried over Na₂SO₄, and concentrated at reduced pressure. Theresidue was purified by MPLC (70% to 90% EtOAc/hexane) to give 799 mg(91%) of the desired product. ¹H-NMR (DMSO-d₆) δ 7.85 (d, J=8.4 Hz, 1H),7.61 to 7.55 (m, 3H), 5.40 (s, 1H), 5.38 (broad s, 2H), 3.46 (t, J=4.5Hz, 4H), 2.88 (q, J=6.0 Hz, 2H), 2.60 (s, 3H), 2.27 to 2.18 (m, 6H),1.20 (s, 9H); MS LC-MS [M+H]⁺=422, RT=1.95 min.

Preparation of3-(5-amino-3-tert-butyl-pyrazol-1-yl)-N-(2-methoxyethyl)-benzenesulfonamide Step 1: Preparation of3-(N′-benzhydrylidenehydrazino)-N-(2-methoxy-ethyl)-benzene sulfonamide

The compound was prepared in the same manner as described for4-(N′-benzhydrylidenehydrazino)-2-methyl-N-(2-morpholin-4-yl-ethyl)benzenesulfonamide, replacing4-bromo-2-methyl-N-(2-morpholin-4-yl-ethyl)benzene sulfonamide with3-bromo-N-(2-methoxyethyl)benzene sulfonamide. ¹H-NMR (DMSO-d₆) δ 9.32(s, 1H), 7.67 (t, J=2.1 Hz, 1H), 7.63 to 7.48 (m, 4H), 7.46 to 7.41 (m,3H), 7.39 to 7.26 (m, 6H), 7.15 to 7.12 (m, 1H), 3.29 (t, 5.7 Hz, 2H),3.15 (s, 3H), 2.87 (q, J=5.7 Hz, 2H); MS LC-MS [M+H]⁺=410, RT=3.50 min.

Step 2: Preparation of3-(5-amino-3-tert-butyl-pyrazol-1-yl)-N-(2-methoxyethyl)-benzenesulfonamide

The title compound was prepared in the same manner as described for4-(N′-benzhydrylidenehydrazino)-2-methyl-N-(2-morpholin-4-yl-ethyl)benzenesulfonamide, replacing4-(N′-benzhydrylidene-hydrazino)-2-methyl-N-(2-morpholin-4-yl-ethyl)-benzenesulfonamide with3-(N′-benzhydrylidenehydrazino)-N-(2-methoxyethyl)-benzene sulfonamide.¹H-NMR (DMSO-d₆) δ 8.00 (s, 1H), 7.86 to 7.79 (m, 2H), 7.63 (dd, J=3.6Hz, 1.5 Hz, 2H), 5.42 (s, 1H), 5.33 (s, 2H), 3.30 (t, J=5.7 Hz, 2H),3.14 (s, 3H), 2.91 (q, J=5.7 Hz, 2H), 1.20 (s, 9H); MS LC-MS [M+H]⁺=353,RT=2.50 min.

Preparation of{5-tert-butyl-2-[3-(2-methoxyethylsulfamoyl)-phenyl]-2H-pyrazol-3-yl}-carbamicacid phenyl ester

To a mixture of3-(5-amino-3-tert-butyl-pyrazol-1-yl)-N-(2-methoxyethyl)benzenesulfonamide (940 mg, 2.67 mmol) and solid sodium carbonate (493 mg, 5.87mmol, 2.2 eq) in anhydrous THF was slowly added phenylchloroformate(0.40 mL, 3.20 mmol, 1.2 eq), and the reaction mixture was stirred atroom temperature under nitrogen for 6 h. The reaction mixture was pouredinto ethyl acetate, and then the organic phase was separated and washedwith water and brine, dried over Na₂SO₄, filtered, and concentrated atreduced pressure. Purification by MPLC (35% EtOAc/hexane) afforded thetitle compound (887 mg, 70%) as a white solid. ¹H-NMR (CD₃OD) δ 10.17(broad s, 1H), 7.94 (t, J=1.5 Hz, 1H), 7.89 (t, J=6.0 Hz, 1H), 7.81 to7.69 (m, 3H), 7.34 to 7.29 (m, 2H), 7.19 (t, J=7.2 Hz, 1H), 7.09 (broads, 2H), 6.38 (s, 1H), 3.25 (t, J=6.0 Hz, 2H), 3.09 (s, 3H), 2.90 (broads, 2H), 1.26 (s, 9H).

Preparation of ethyl[4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenyl]acetate hydrochlorideStep 1. Preparation of ethyl (4-hydrazinophenyl)acetate hydrochloride

A solution of sodium nitrite (NaNO₂, 4.04 g, 58.6 mmol) in H₂O (20 mL)was added to a cooled (−5° C., ice-salt) solution of ethyl4-aminophenylacetate (10 g, 55.8 mmol) in conc. HCl (55 mL), at a ratesuch that the temperature did not exceed 0° C. The mixture was stirredat 0° C. for 10 min and then added portion-wise to a cooled (−5° C.,ice-salt) and rapidly-stirred solution of tin(II) chloride (SnCl₂, 39.67g, 209.2 mmol) in conc. HCl (30 mL), at a rate such that the temperaturedid not exceed 0° C. The resulting cream-colored suspension was warmedto 25° C. and stirred at room temperature for 2-3 hrs and then wasfiltered under vacuum. The collected solid was washed with water andether and then air dried to afford the desired product as a pale solid(HCl salt). Precipitate that formed in the filtrates upon standing for16 h was collected by filtration, washed with water and ether, andair-dried. The combined solids were obtained in 88% yield (11.28 g).¹H-NMR (DMSO-d₆) δ 8.85 (broad, 2H), 7.73 (broad, 1H), 7.10 (d, J=8.4Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 4.03 (q, J=7.0 Hz, 2H), 3.53 (s, 2H),1.16 (t, J=7.1 Hz, 3H); MS LC-MS [M+H]⁺=195.0, RT=1.11 min.

Step 2. Preparation of ethyl[4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenyl]acetate hydrochloride

The title compound was prepared in the same manner as described for5-tert-butyl-2-(4-nitro-phenyl)-2H-pyrazol-3-ylamine, replacing4-nitrophenylhydrazine with ethyl (4-hydrazinophenyl)acetatehydrochloride (11.98 g, 51.9 mmol). The title compound was obtained as awhite solid (HCl salt, 11.95 g) in 68% yield. ¹H-NMR (DMSO-d₆) δ 7.52(d, J=8.4 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 5.59 (s, 1H), 4.08 (q, J=7.1Hz, 2H), 3.77 (s, 2H), 1.27 (s, 9H), 1.20 (t, J=7.1 Hz, 3H); MS LC-MS[M+H]⁺=302.3, RT=2.44 min.

Preparation of ethyl(4-[3-tert-butyl-5-[(phenoxycarbonyl)amino]-1H-pyrazol-1-yl]phenyl)acetate

To a suspension of ethyl[4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenyl]acetate (10 g, 33.2mmol) and K₂CO₃ (9.17 g, 66.4 mmol) in THF (300 mL) was added phenylchloroformate (8.61 mL, 66.4 mmol), and the resulting reaction mixturewas stirred at room temperature overnight. The mixture was poured into amixture of water and EtOAc and the organic phase was separated and driedover Na₂SO₄, concentrated at reduced pressure to afford a brown syrup,which was purified by MPLC (0% to 20% EtOAc in hexane). The desiredproduct was obtained as a white solid (10.6 g) in 76% yield. ¹H-NMR(CD₂Cl₂-d₂) δ 7.51-7.10 (m, 10H), 6.47 (s, 1H), 4.16 (q, J=7.1 Hz, 2H),3.71 (s, 2H), 1.37 (s, 9H), 1.28 (t, J=7.0 Hz, 3H).

Preparation of4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)phenyl]ureido}-pyrazol-1-yl)benzoicacid methyl ester

To a suspension of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)benzoic acidmethyl ester (1.89 g, 6.93 mmol) in anhydrous DCE (10 mL) was added CDI(1.24 g, 7.62 mmol), and the mixture was stirred at room temperature for16 h. A suspension of 4-(pyridin-4-yloxy)phenylamine (1.29 g, 6.93 mmol;Dumas et al., U.S. pat. appl. US2002065296 (2002)) in DCE was thenadded, and the mixture was stirred at room temperature for 4 h. Thereaction was diluted into EtOAc. The organic layer was washed with waterand brine, dried over MgSO₄, filtered, and concentrated at reducedpressure. The crude product was purified by MPLC (15% EtOAc/hexane) togive 2.3 g (68%) of the title compound as a white solid. ¹H-NMR(acetone-d₆) δ 8.64 (s, 1H), 8.44 (d, J=9.0 Hz, 2H), 8.12 (d, J=9.0 Hz,2H), 8.01 (s, 1H), 7.61 (d, J=9.0 Hz, 2H), 7.81 (d, J=9.0 Hz, 2H), 7.09(d, J=9.0 Hz, 2H), 6.86 (d, J=6.0 Hz, 2H), 6.48 (s, 1H), 3.91 (s, 3H),1.34 (s, 9H); MS LC-MS [M+H]⁺=486, RT=2.50 min.

Preparation of4-(3-tert-butyl-5-{3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzoicacid methyl ester

A solution of4-(3-tert-butyl-5-phenoxycarbonylamino-pyrazol-1-yl)benzoic acid methylester (470 mg, 1.19 mmol) and2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl-amine (260.69 mg, 1.19mmol) was stirred at 40° C. overnight. The mixture was cooled to roomtemperature, and then evaporated at reduced pressure. The residue waspurified by MPLC (eluting with 50:50 EtOAc/hexane) to afford the titlecompound (407 mg, 66%). ¹H-NMR (DMSO-d₆) δ 8.94 (s, 2H), 8.30 (d, J=5.7Hz, 1H), 8.09 (m, 3H), 7.71 (d, J=5.7 Hz, 2H), 7.20 (d, J=14.7, 1H),6.94 (d, J=5.4 Hz, 1H), 6.77 (d, J=2.7 Hz, 1H), 6.72 (d, J=5.4 Hz, 1H),6.42 (s, 1H), 3.87 (s, 3H), 2.38 (s, 3H), 1.27 (s, 9H); MS LC-MS[M+H]⁺=518.2, RT=2.94 min.

Preparation of3-(3-tert-butyl-5-{3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzoicacid

To a solution of3-(3-tert-butyl-5-{3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzoicacid methyl ester (2.0 g, 4.12 mmol; prepared in a similar manner asdescribed for4-(3-tert-butyl-5-{3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzoicacid methyl ester) in methanol, was added potassium hydroxide (692 mg,12.4 mmol) in water. The mixture was stirred at 40° C. overnight, thencooled to room temperature. Methanol was evaporated at reduced pressure,and the aqueous residue neutralized to pH 7 by addition of 2N HCl. Thewhite solid that formed was collected by filtration and dried in vacuoto give the title compound (1.9 g, 98%). ¹H-NMR (DMSO-d₆) δ 8.95 (s,1H), 8.92 (s, 1H), 8.30 (d, J=5.7 Hz, 1H), 8.11-8.03 (m, 2H), 7.94 (d,10.2 Hz, 1H), 7.79 (d, J=9.9 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.18(J=14.1 Hz, 1H), 6.95 (d, J=12.9 Hz, 1H), 6.75 (m, 2H), 6.39 (s, 1H),2.39 (s, 3H), 1.89 (s, 9H); MS LC-MS [M+H]⁺=504.2, RT=2.47 min.

Preparation of1-[5-tert-butyl-2-(4-nitro-phenyl)-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea

To a solution of 5-tert-butyl-2-(4-nitrophenyl)-2H-pyrazol-3-ylamine(5.0 g, 19.2 mmol) in anhydrous DCE (2 mL) was added CDI (3.5 g, 21.1mmol), and the reaction was stirred under N₂ at room temperature for 18h. 4-(Pyridin-4-yloxy)phenylamine (3.3 g, 17.7 mmol, Dumas et al., U.S.pat. appl. US2002065296 (2002)) in DCE (12 mL) was added to thereaction, and the solution was stirred under N₂ at room temperature for7 h. The reaction mixture was partitioned between EtOAc (100 mL) andwater (100 mL). The organic layer was washed with brine, dried overNa₂SO₄, and concentrated at reduced pressure. The crude residue waspurified by MPLC (1:1 hexanes/EtOAc) to give 5.6 g (68%) of the desiredproduct. ¹H-NMR (DMSO-d₆) δ 9.21 (s, 1H), 8.68 (s, 1H), 8.43 (d, J=6.3Hz, 2H), 8.36 (d, J=7.2 Hz, 2H), 7.90 (d, J=6.9 Hz, 2H), 7.50 (d, J=6.9Hz, 2H), 7.09 (d, J=6.6 Hz, 2H), 6.86 (d, J=5.7 Hz, 2H), 6.44 (s, 1H),1.29 (s, 9H); MS LC-MS [M+H]⁺=473, RT=2.60 min.

Preparation of1-[2-(4-aminophenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea

A solution of1-[5-tert-butyl-2-(4-nitrophenyl)-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea(2.5 g, 5.3 mmol) in anhydrous EtOH (40 mL) was added to a round bottle(100 mL) flask containing 10% Pd/C (30 mg). The reaction vessel wasfitted with a balloon adapter and charged with hydrogen and evacuatedthree times until the reaction was under a H₂ atmosphere. The reactionmixture was stirred at room temperature for 18 h, and then filteredthrough a pad of celite. The celite was washed with EtOH (200 mL) andthe filtrate was concentrated at reduced pressure. The residue waspurified by MPLC (1:1 hexanes/EtOAc) to give 1.8 g (77%) of the desiredproduct. ¹H-NMR (DMSO-d₆) δ 9.16 (s, 1H), 8.42 (d, J=5.4 Hz, 2H), 8.17(s, 1H), 7.47 (d, J=6.9 Hz, 2H), 7.09 to 7.04 (m, 4H), 6.86 (d, J=5.7Hz, 2H), 6.64 (d, J=6.6 Hz, 2H), 6.28 (s, 1H), 6.38 (s, 2H), 1.18 (s,9H); MS LC-MS [M+H]⁺=443, RT=1.95 min.

Preparation of1-[5-tert-butyl-2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]urea

The title compound was prepared by CDI coupling (35% yield) in the samemanner as described for1-[5-tert-butyl-2-(4-nitro-phenyl)-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]urea,replacing 5-tert-butyl-2-(4-nitrophenyl)-2H-pyrazol-3-ylamine with1-[5-tert-butyl-2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]urea.¹H-NMR (DMSO-d₆) δ 9.18 (s, 1H), 8.60 (s, 1H), 8.41 (d, J=5.4 Hz, 2H),7.98 (d, J=6.9 Hz, 2H), 7.80 (d, J=6.9 Hz, 2H), 7.48 (d, J=6.6 Hz, 2H),7.08 (d, J=6.6 Hz, 2H), 6.84 (d, J=5.4 Hz, 2H), 6.40 (s, 1H), 1.26 (s,9H); MS LC-MS [M+H]⁺=453, RT=2.37 min.

Preparation of 4-(pyridin-3-yloxy)aniline

Step 1. Preparation of 3-(4-nitrophenoxy)pyridine

To a solution of 1-fluoro-4-nitrobenzene (50.00 g, 354.36 mmol) in DMF(450 ml) was added 3-hydroxypyridine (33.70 g, 354.36 mmol) undernitrogen. The reaction mixture was heated to 35° C. and then potassiumcarbonate (102.85 g, 744.15 mmol) was added in one portion. The reactionwas very exothermic, and the temperature rapidly increased to 115° C.,then gradually increased to 125° C. The mixture was then cooled to 90°C. and stirred at 90° C. for 2 h. The mixture was cooled to roomtemperature and poured into 2.5 L of water. The mixture was extractedwith ethyl acetate (3×), and the combined organic phases were washedwith water (3×) and brine (1×), dried over sodium sulfate, andevaporated at reduced pressure. The brown solid residue was stirred inMTBE at reflux, then filtered, and the filtrate was concentrated atreduced pressure to give a yellow crystalline solid that was trituratedwith ether to give 23.79 g (31%) of the desired product. The brownsolids that did not dissolve in MTBE (43.89 g, 57%) were also ofsufficient purity for use in the next step (i.e., total yield 88%).¹H-NMR (DMSO-d₆) δ 8.50 (m, 2H), 8.24 (d, J=9.1 Hz, 2H), 7.67 (ddd,J=8.4, 2.9, 1.3 Hz, 1H), 7.52 (dd, J=8.3, 4.7 Hz, 1H), 7.18 (d, J=9.0Hz, 2H); MS LC-MS [M+H]⁺=217, RT=1.67 min. In a subsequent experiment,the potassium carbonate was added to the 1-fluoro-4-nitrobenzene in DMFunder nitrogen. To this stirred solution was dropwise added a solutionof the 3-hydroxypyridine in DMF, and the exotherm caused the mixture togradually warm up to 38° C. The reaction mixture was then heated to 60°C. for 2 h. Reaction work up as described above gave the desiredproduct.

Step 2. Preparation of 4-(pyridin-3-yloxy)aniline

A solution of 3-(4-nitrophenoxy)pyridine (5.00 g, 23.13 mmol) in EtOAc(100 mL) in a 250 ml Parr bottle was purged with nitrogen. To thissolution was added EtOAc-moistened 10% Pd/C catalyst (500 mg, 10% byweight). The reaction flask was placed in a Parr hydrogenationapparatus, purged with nitrogen (5×), evacuated, and then pressurized to40 psi with hydrogen and shaken for 3.5 h. The reaction mixture was thenpurged with nitrogen, and filtered through a pad of Celite®, rinsingwith ethyl acetate (3×) and ethanol (3×). The filtrate was evaporated atreduced pressure to give a brown crystalline residue. The residue wasstirred in diethyl ether at room temperature for 16 h and then filteredto provide 4.11 g (95%) of the desired product as light brown crystals.¹H-NMR (DMSO-d₆) δ 8.21 (m, 2H), 7.30 (ddd, J=8.4, 4.6, 0.7 Hz, 1H),7.18 (ddd, J=8.4, 2.9, 1.4 Hz, 1H), 6.79 (d, J=8.8 Hz, 2H), 6.58 (d,J=9.0 Hz, 2H), 5.05 (br s, 2H); MS LC-MS [M+H]⁺=187, RT=1.03 min.

Preparation of 2-fluoro-4-(2-methylpyridin-4-yloxy)phenylamine

A solution of 4-amino-3-fluorophenol (5.00 g, 39.3 mmol) in anhydrousDMA (100 mL) was treated with potassium tert-butoxide (5.30 g, 47.2mmol), and the red-brown mixture was stirred at room temperature for 1h. The mixture was treated with a solution of 4-chloro-2-picoline (5.02g, 39.3 mmol) in anhydrous DMA (75 mL) and then heated at 100° C. for 17h. The mixture was cooled to ambient temperature and partitioned betweenEtOAc (500 mL) and saturated NaCl solution (500 mL). The aqueous phasewas back-extracted with EtOAc (300 mL). The combined organic phases werewashed with brine, dried over Na₂SO₄, and concentrated at reducedpressure. Purification through a silica gel plug, eluting with 40%EtOAc/hexane, followed by crystallization from DCM/hexane afforded 4.06g (47%) of the title compound as a yellow solid. ¹H-NMR (DMSO-d₆) δ 8.24(d, J=5.4 Hz, 1H), 6.91 (dd, J=12.3, 2.7 Hz, 1H), 6.80 (dd, J=9.6, 8.7Hz, 1H), 6.72 to 6.62 (m, 3H), 5.15 (broad s, 2H), (2.36 (s, 3H); MSLC-MS [M+H]⁺=219, RT=0.24 min.

EXAMPLES Example 14-{3-tert-Butyl-5-[({[4-(pyridin-4-yloxy)-phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-pyrrolidin-1-ylethyl)benzamide

To a solution of 2-pyrrolidin-1-yl-ethylamine in DCE was added trimethylaluminum (1.03 mmol, 0.51 mL of 2N solution in DCM). After the reactionwas stirred at ambient temperature for 30 minutes, a solution of4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)phenyl]ureido}pyrazol-1-yl}benzoicacid methyl ester (100 mg, 0.21 mmol) in DCE was added, and the reactionmixture was stirred at 80° C. for 16 h. The reaction mixture wasquenched with two drops of water, dried over MgSO₄, filtered, andevaporated at reduced pressure. Purification using MPLC (eluting with15% NH₃ in MeOH (2N)/EtOAc) afforded 34 mg (29%) of the title compound.¹H-NMR (acetone-d₆) δ 8.43 (d, J=9.0 Hz, 2H), 7.94 (d, J=9.0 Hz, 2H),7.69 (d, J=9.0 Hz, 2H), 7.60 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H),6.84 (d, J=4.0 Hz, 2H), 6.48 (s, 1H), 3.52 (t, J=7.5 Hz, 2H), 2.67 (t,J=3.0 Hz, 2H), 2.50 to 2.64 (m, 4H), 1.70 to 1.72 (m, 4H), 1.31 (s, 9H);MS LC-MS [M+H]⁺=568, RT=2.48 min.

Example 2N-{3-tert-Butyl-1-[4-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)-phenyl]urea

To a solution of5-tert-butyl-2-[4-(2-methoxyethoxy)phenyl]2H-pyrazol-3-ylamine (75 mg,0.26 mmol) in anhydrous DCE (1.0 mL) was added CDT (37 mg, 0.31 mmol),and the reaction mixture was stirred at 60° C. for 6 h. A solution of4-(pyridin-4-yloxy)phenylamine (48 mg, 0.26 mmol) in DCE (1.3 mL) wasthen added, and the mixture was stirred at 60° C. for 20 h. The reactionmixture was diluted into EtOAc. The organic layer was washed with waterand brine, dried over Na₂SO₄, filtered, and concentrated at reducedpressure. The crude product was purified by HPLC and recrystallized fromether/DCM/hexane to give 45.2 mg (35%) of the title compound as a whitesolid. ¹H-NMR (DMSO-d₆) δ 9.01 (s, 1H), 8.39 (d, J=4.8 Hz, 2H), 8.28 (s,1H), 7.46 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.7 Hz, 2H), 7.05 (d, J=8.7 Hz,4H), 6.84 (d, J=4.8 Hz, 2H), 6.29 (s, 1H), 4.14 to 4.10 (m, 2H), 3.66 to3.63 (m, 2H), 3.28 (s, 3H), 1.23 (s, 9H); MS LC-MS [M+H]⁺=502, RT=2.80min.

Example 3N-[3-tert-Butyl-1-[4-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl]urea

The title compound was prepared in the same manner as described for1-{5-tert-butyl-2-[4-(2-methoxyethoxy)phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-4-yloxy)-phenyl]-urea,replacing 4-(pyridin-4-yloxy)phenylamine with2-fluoro-4-(2-methyl-pyridin-4-yloxy)phenyl-amine. ¹H-NMR (DMSO-d₆) δ8.96 (s, 1H), 8.74 (s, 1H), 8.29 (d, J=6.0 Hz, 1H), 8.14 (t, J=9.3 Hz,1H), 7.38 (d, J=9.0 Hz, 2H), 7.18 (d, J=9.0 Hz, 1H), 7.08 (dd, J=11.7,2.4 Hz, 2H), 6.95 (d, J=7.5 Hz, 1H), 6.76 (d, J=2.4 Hz, 1H), 6.73 to6.70 (m, 1H), 6.34 (s, 1H), 4.16 to 4.12 (m, 2H), 3.68 to 3.65 (m, 2H),3.30 (s, 3H), 2.38 (s, 3H), 1.24 (s, 9H); MS LC-MS [M+H]⁺=534, RT=2.39min.

Example 4N-(3-tert-Butyl-1-{4-[2-(diethylamino)ethoxy]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea

To 4-(pyridin-4-loxy)phenylamine (75.0 mg, 0.40 mmol) in anhydrous THF(4.0 mL) was added triphosgene (48 mg, 0.16 mmol) andN,N′-diisopropylethyl amine (63 mg, 0.48 mmol), and the reaction mixturewas stirred at 75° C. for 3 h. A solution of5-tert-butyl-2-[4-(2-diethylaminoethoxyphenyl]-2H-pyrazol-3-ylamine (133mg, 0.40 mmol) in anhydrous THF (2.0 mL) was added, and the reactionmixture was stirred at 75° C. for 17 h. The reaction was partitionedbetween EtOAc and saturated aqueous NH₄Cl solution. The organic layerwas washed with water and brine, dried over Na₂SO₄, filtered, andconcentrated at reduced pressure. Purification using MPLC (eluting with10 to 15% MeOH/EtOAc) and crystallization from ether/hexane afforded65.7 mg (30%) of the title compound as a tan solid. ¹H-NMR (DMSO-d₆) δ9.08 (s, 1H), 8.40 (dd, J=4.5, 1.8 Hz, 2H), 8.28 (s, 1H), 7.46 (dd,J=6.6, 2.1 Hz, 2H), 7.37 (dd, J=6.9, 2.1 Hz, 2H), 7.08 to 7.02 (m, 4H),6.84 (dd, J=4.8, 1.8 Hz, 2H), 6.30 (s, 1H), 4.04 (t, J=6.6 Hz, 2H), 2.77(t, J=5.7 Hz, 2H), 2.53 (q, J=6.9 Hz, 4H), 1.24 (s, 9H), 0.95 (t, J=6.9Hz, 6H); MS LC-MS [M+H]⁺=543, RT=2.16 min.

Example 51-{5-tert-Butyl-2-[4-(2-piperidin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-3-yloxy)-phenyl]-urea

Step 1.4-{2-[4-(5-Amino-3-tert-butyl-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester was coupled with 4-(pyridin-3-yloxy)phenylamine byreaction with CDI in a similar manner to that described above, toprovide the urea4-{2-[4-(3-tert-butyl-5-{3-[4-(pyridin-3-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (LC-MS [M+H]⁺=655, RT=3.51 min).

Step 2. To a solution of4-{2-[4-(3-tert-butyl-5-{3-[4-(pyridin-3-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (210 mg, 0.32 mmol) in DCM (1 mL) was addedtrifluoroacetic acid (0.3 mL). The reaction mixture was stirred at roomtemperature for 16 h, concentrated at reduced pressure, re-dissolved inmethanol and purified by preparative HPLC. The HPLC fraction containingthe desired product was basified by addition of saturated aq Na₂CO₃ andthen extracted with EtOAc. Evaporation of the solvent at reducedpressure gave the desired product1-{5-tert-butyl-2-[4-(2-piperidin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-3-yloxy)-phenyl]-urea(46.6 mg, 26%). ¹H-NMR (DMSO-d₆) δ 9.20 (s, 1H), 8.30 (m, 3H), 7.45-7.35(m, 5H), 7.00 (m, 3H), 6.30 (s, 1H), 4.0 (m, 4H), 2.40 (m, 2H),1.70-1.60 (m, 6H), 1.40 (s, 9H), 1.05 (m, 1H); MS LC-MS [M+H]⁺=555.3,RT=2.73 min.

Example 61-{5-tert-Butyl-2-[3-(3-hydroxy-propoxy)-phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-4-yloxy)-phenyl]-urea

Step 1. To a solution of3-[3-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenoxy]-propan-1-ol (400 mg,1.38 mmol) and phenyl chloroformate (324 mg, 2.07 mmol) in THF (14 mL)was added cesium carbonate (673 mg, 2.07 mmol). The mixture was stirredat room temperature for 4 h, additional phenyl chloroformate (108 mg,0.69 mmol) was added, and then the mixture was stirred for an additionaltwo hours. The reaction mixture was washed with saturated NaHCO₃ (3×30mL), water, brine, dried (Na₂SO₄), and evaporated at reduced pressure togive the crude carbamate intermediate{5-tert-butyl-2-[3-(3-hydroxy-propoxy)-phenyl]-2H-pyrazol-3-yl}-carbamicacid phenyl ester (500 mg).

Step 2. To a solution of{5-tert-butyl-2-[3-(3-hydroxy-propoxy)-phenyl]-2H-pyrazol-3-yl}-carbamicacid phenyl ester (200 mg, 0.49 mmol) in THF was added4-(pyridin-4-yloxy)-phenylamine (109 mg, 0.59 mmol). The reactionmixture was heated at 60° C. for 16 h. The reaction mixture was cooledto room temperature, concentrated at reduced pressure, and the residuewas dissolved in DMF and methanol. The product was isolated bypreparative HPLC, and the HPLC fraction containing the desired productwas concentrated at reduced pressure and then partitioned between EtOAc(20 mL) and saturated aq Na₂CO₃ (10 mL). The organic layer was driedover Na₂SO₄ and evaporated to give1-{5-tert-butyl-2-[3-(3-hydroxy-propoxy)-phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-4-yloxy)-phenyl]-urea(51.3 mg, 21%). ¹H-NMR (DMSO-d₆) δ 7.50 (d, 2H), 7.10 (m, 5H), 6.90 (d,2H), 6.70 (m, 3H), 6.40 (s, 1H), 4.0 (t, 2H), 3.60 (t, 3H), 1.80 (m,2H), 1.30 (s, 9H); MS LC-MS [M+H]⁺=502.1, RT=2.36 min.

Example 7N-(4-{3-tert-Butyl-5-[({[4-(pyridin-4-yloxy)-phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-3-methoxypropanamide

To a solution of1-[2-(4-aminophenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea(200 mg, 0.45 mmol) and 3-methoxypropionyl chloride (55 mg, 0.45 mmol)in anhydrous THF (5 mL) was added Et₃N (69 mg, 0.68 mmol). The reactionwas stirred at room temperature for 7 h, and then partitioned betweenEtOAc (50 mL) and water (50 mL). The organic layer was washed withbrine, dried over Na₂SO₄, and concentrated at reduced pressure. Theresidue was purified by MPLC (1:1 hexanes/EtOAc) to give 51 mg (21%) ofthe desired product. ¹H-NMR (DMSO-d₆) δ 10.16 (s, 1H), 9.14 (s, 1H),8.42 (d, J=4.8 Hz, 2H), 8.34 (s, 1H), 7.74 (d, J=6.9 Hz, 2H), 7.48 (d,J=6.9 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H), 7.08 (d, J=6.6 Hz, 2H), 6.88 (d,J=5.4 Hz, 2H), 6.35 (s, 1H), 3.63 (t, J=6.0 Hz, 2H), 3.33 (s, 3H), 2.57(t, J=6.0 Hz, 2H), 1.27 (s, 9H); MS LC-MS [M+H]⁺=529, RT=2.20 min.

Example 8N-(3-tert-Butyl-1-{4-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea

To a solution ofN-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]-phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)phenyl]-2-methoxyacetamide(500 mg, 0.97 mmol) in anhydrous THF (20 mL) was added borane-methylsulfide complex (2.0 M solution in THF, 5 mL, 10 mmol), and the reactionwas stirred at reflux for 7 h. The reaction mixture was cooled to roomtemperature, partitioned between EtOAc (50 mL) and water (50 mL), andthe organic layer was washed with brine, dried over Na₂SO₄, andconcentrated at reduced pressure. The residue was purified by MPLC (1:1hexanes/EtOAc) to give 33 mg (7%) of the desired product. ¹H-NMR(DMSO-d₆) δ 8.65 (s, 1H), 8.42 (d, J=4.8 Hz, 2H), 8.34 (s, 1H), 7.58 (d,J=6.6 Hz, 2H), 7.21 (d, J=6.6 Hz, 2H), 7.06 (d, J=6.9 Hz, 2H), 6.84 (d,J=4.8 Hz, 2H), 6.73 (d, J=6.9 Hz, 2H), 6.43 (s, 1H), 5.23 (s, 1H), 3.57(t, J=5.7 Hz, 2H), 3.35 to 3.30 (m, 5H), 1.32 (s, 9H); MS LC-MS[M+H]⁺=529, RT=2.20 min.

Example 9N-[4-(3-tert-Butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenyl]-2,2-dimethyl-succinamicacid

A solution of1-[2-(4-amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea(208 mg, 0.47 mmol) and 2,2-dimethylsuccinic anhydride (66 mg, 0.52mmol, 1.1 eq) in 2 mL THF was stirred at room temperature overnight.HPLC analysis indicated that starting material was remaining. Thereaction was then heated at 60° C. for 2 days, at which time HPLCanalysis indicated the reaction was complete. The reaction mixture wascooled to room temperature, and the resulting suspension was dilutedwith Et₂O. The solid was isolated by filtration to afford the desiredproduct (227 mg, 85%). ¹H-NMR (DMSO-d₆) δ 12.06 (s, 1H), 10.06 (s, 1H),9.09 (s, 1H), 8.40 (d, J=6.0 Hz, 2H), 8.31 (s, 1H), 7.69 (d, J=9.0 Hz,2H), 7.47 (d, J=9.0 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0 Hz,2H), 6.85 (dd, J=1.5 & 4.7 Hz, 2H), 6.33 (s, 1H), 2.59 (s, 2H), 1.26 (s,9H), 1.21 (s, 6H); MS LC-MS [M+H]⁺=571.3, RT=2.49 min.

Example 101-{5-tert-Butyl-2-[4-(4-hydroxy-3,3-dimethyl-butylamino)-phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-4-yloxy)-phenyl]-urea

A solution ofN-[4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenyl]-2,2-dimethyl-succinamicacid (190 mg, 0.33 mmol) in 3 mL THF was treated withborane-methylsulfide complex (2M, 1.0 mL, 2.0 mmol, 6 eq). The reactionmixture was heated at reflux under nitrogen for 4 h. The reactionmixture was then cooled to room temperature, slowly quenched by theaddition of 0.6 mL EtOH and 2 mL 2N HCl. The reaction mixture was heatedagain at reflux for 1 hr, then cooled to room temperature, basified bythe addition of 1N NaOH, extracted with DCM, and concentrated at reducedpressure. The crude residue was purified by MPLC (eluting with 2% to 6%MeOH in DCM) to afford 80 mg of semi-pure1-[2-(4-amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea.Preparative HPLC purification using 5-80% H₂O in acetonitrile(containing 0.5% TFA) afforded 33 mg (18%) of the desired product.¹H-NMR (DMSO-d₆) δ 9.14 (s, 1H), 8.40 (dd, J=1.6 & 4.8 Hz, 2H), 8.17 (s,1H), 7.47 (d, J=8.9 Hz, 2H), 7.11 (d, J=8.6 Hz, 2H), 7.07 (d, J=9 Hz,2H), 6.85 (dd, J=1.5 & 4.9 Hz, 2H), 6.62 (d, J=8.9 Hz, 2H), 6.28 (s,1H), 5.83 (t, J=5.2 Hz, 1H), 4.58 (t, J=5.2 Hz, 1H), 3.14 (d, J=5.4 Hz,2H), 3.06-3.01 (m, 2H), 1.52-1.48 (m, 2H), 1.25 (s, 9H), 0.87 (s, 6H);MS LC-MS [M+H]⁺=543.2, RT=2.31 min.

Example 111-{5-tert-Butyl-2-[3-(3-hydroxy-propylamino)-phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-4-yloxy)-phenyl]-urea

Step 1: To a solution of1-[2-(3-amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea(100 mg, 0.23 mmol), 3-[(tert-butyldimethylsilyl)oxy]-1-propanal (47 mg,0.25 mmol, 1.1 eq), and sodium triacetoxyborohydride (67 mg, 0.32 mmol,1.4 eq) in anhydrous THF (2 mL) was added acetic acid (16 mg, 0.27 mmol,1.2 eq). The reaction mixture was stirred under N₂ at room temperaturefor 2 h. The reaction mixture was quenched with saturated NaHCO₃ andextracted with EtOAc. The combined organic phases were washed withbrine, dried over Na₂SO₄ and concentrated at reduced pressure. The cruderesidue was purified by MPLC (eluting with 40:60 to 60:40 EtOAc/hexanes)to give 117 mg (84%) of1-(5-tert-butyl-2-{3-[3-(tert-butyl-dimethyl-silanyloxy)-propylamino]-phenyl}-2H-pyrazol-3-yl)-3-[4-(pyridin-4-yloxy)-phenyl]-urea.¹H-NMR (DMSO-d₆) δ 9.17 (s, 1H), 8.40 (dd, J=1.5 & 4.6 Hz, 2H), 8.31 (s,1H), 7.48 (d, J=8.8 Hz, 2H), 7.17 (t, J=8.1 Hz, 1H), 7.07 (d, J=8.8 Hz,2H), 6.85 (dd, J=1.6 & 4.9 Hz, 2H), 6.61-6.56 (m, 3H), 6.32 (s, 1H),5.92 (t, J=5.6 Hz, 1H), 3.66 (t, J=6.1 Hz, 2H), 3.07 (q, J=7.5 Hz, 2H),1.72 (quintet, J=6.8 Hz, 2H), 1.26 (s, 9H), 0.84 (s, 9H), 0.02 (s, 6H);MS LC-MS [M+H]⁺=615.4, RT=3.28 min.

Step 2: To a solution of1-(5-tert-butyl-2-{3-[3-(tert-butyl-dimethyl-silanyloxy)-propylamino]-phenyl}-2H-pyrazol-3-yl)-3-[4-(pyridin-4-yloxy)-phenyl]-urea(117 mg, 0.19 mmol) in methanol (2 mL) was added a solution of 10% TFAin H₂O (2 mL). The reaction was stirred at room temperature overnight.The mixture was then diluted with DCM, basified by the addition ofsaturated aq NaHCO₃ and extracted with DCM. The combined organic phaseswere washed with brine, dried over MgSO₄, and concentrated at reducedpressure. The crude residue was purified by MPLC (eluting with 4% to5.5% MeOH in DCM) to give 82 mg (86%) of the desired product1-{5-tert-butyl-2-[3-(3-hydroxy-propylamino)-phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-4-yloxy)-phenyl]-urea.¹H-NMR (DMSO-d₆) δ 9.18 (s, 1H), 8.40 (dd, J=1.7 & 4.7 Hz, 2H), 8.32 (s,1H), 7.48 (d, J=9.0 Hz, 2H), 7.17 (t, J=7.9 Hz, 1H), 7.07 (d, J=9.1 Hz,2H), 6.85 (dd, J=1.5 & 4.7 Hz, 2H), 6.63-6.56 (m, 3H), 6.33 (s, 1H),5.91 (t, J=5.3 Hz, 1H), 4.47 (t, J=5.1 Hz, 1H), 3.48 (q, J=6.1 Hz, 2H),3.06 (q, J=6.6 Hz, 2H), 1.69 (quintet, J=6.5 Hz, 2H), 1.26 (s, 9H); MSLC-MS [M+H]⁺=501.2, RT=2.29 min.

Example 12N-(3-tert-Butyl-1-{3-[[(dimethylamino)sulfonyl](3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea

A solution of1-{5-tert-butyl-2-[3-(3-hydroxy-propylamino)-phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-4-yloxy)-phenyl]-urea(100 mg, 0.21 mmol) in THF (1 mL) was treated with dimethylsulfamoylchloride (90 mg, 0.62 mmol, 3 eq) followed by DIEA (30 mg, 0.21 mmol, 1eq). The reaction mixture was stirred at 40° C. overnight. The mixturewas evaporated at reduced pressure, and the product was isolated by MPLC(eluting with 1% to 4% MeOH in DCM) to afford 57 mg (46%) of desiredproduct. ¹H-NMR (DMSO-d₆) δ 9.08 (s, 1H), 8.40-8.38 (m, 3H), 7.54-7.36(m, 6H), 7.05 (d, J=8.9 Hz, 2H), 6.84 (d, J=5.6 Hz, 2H), 6.32 (s, 1H),4.45 (t, J=4.6 Hz, 1H), 3.64 (t, J=7.0 Hz, 2H), 3.33-3.28 (m, 2H), 2.70(s, 6H), 1.49-1.45 (m, 2H), 1.29 (s, 9H); MS LC-MS [M+H]⁺=608.2, RT=2.45min.

Example 131-(2-{3-[Bis-(2-hydroxy-ethyl)-amino]-phenyl}-5-tert-butyl-2H-pyrazol-3-yl)-3-[4-(pyridin-4-yloxy)-phenyl]-urea

Step 1: To a solution of1-[2-(3-amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea(124 mg, 0.28 mmol), (tert-butyldimethylsilyloxy)acetaldehyde (135 mg,0.70 mmol, 2.5 eq), and sodium triacetoxyborohydride (178 mg, 0.84 mmol,3 eq) in anhydrous THF (2 mL) was added acetic acid (20 mg, 0.34 mmol,1.2 eq). The reaction was stirred under N₂ at room temperature for 2 h.The reaction mixture was quenched with saturated aq NaHCO₃ and extractedwith EtOAc. The combined organic phases were washed with brine, driedover Na₂SO₄ and concentrated at reduced pressure. The residue waspurified by MPLC (eluting with 45:55 to 65:35 EtOAc/hexanes) to give 153mg (72%) of1-[2-(3-{bis-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-amino}-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea.¹H-NMR (DMSO-d₆) δ 9.17 (s, 1H), 8.39 (d, J=6.3 Hz, 2H), 8.31 (s, 1H),7.47 (d, J=9.0 Hz, 2H), 7.24 (t, J=7.9 Hz, 1H), 7.07 (d, J=9 Hz, 2H),6.84 (d, J=6.1 Hz, 2H), 6.72-6.66 (m, 3H), 6.33 (s, 1H), 3.72 (t, J=5.8Hz, 4H), 3.49 (t, J=5.9 Hz, 4H), 1.26 (s, 9H), 0.82 (s, 18H), −0.01 (s,12H); MS LC-MS [M+H]⁺=760.3, RT=4.10 min.

Step 2: To a solution of1-[2-(3-{bis-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-amino}-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea(153 mg, 0.20 mmol) in methanol (2 mL) was added a solution of 10% TFAin H₂O (2 mL). The reaction was stirred at room temperature for 4 h. Themixture was then diluted with DCM, basified by addition of saturatedNaHCO₃ and extracted with DCM. The combined organic phases were washedwith brine, dried over MgSO₄, and concentrated at reduced pressure. Theresidue was purified by MPLC (eluting with 3% to 6% MeOH in DCM) to give35 mg (36%) of the desired product. ¹H-NMR (DMSO-d₆) δ 9.17 (s, 1H),8.40 (dd, J=1.5 & 4.7 Hz, 2H), 8.32 (s, 1H), 7.48 (d, J=8.8 Hz, 2H),7.26-7.22 (m, 1H), 7.07 (d, J=9.1 Hz, 2H), 6.85 (dd, J=1.5 & 4.7 Hz,2H), 6.71-6.69 (m, 2H), 6.63 (d, J=7.9 Hz, 1H), 6.34 (s, 1H), 4.76 (t,J=5.4 Hz, 2H), 3.54 (q, J=5.7 Hz, 4H), 3.43 (t, J=5.7 Hz, 4H), 1.26 (s,9H); MS LC-MS [M+H]⁺=531.2, RT=2.27 min.

Example 141-[2-(4-Aminomethyl-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]-urea

To a solution of1-[5-tert-butyl-2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea(4.0 g, 8.8 mmol) in anhydrous THF (20 mL) was added a solution oflithium aluminum hydride in THF (1M, 9.7 mL, 9.7 mmol) with stirring at0° C. under nitrogen, and then the reaction mixture was stirred at roomtemperature for 5 h. The excess lithium aluminum hydride was quenched bydropwise addition of EtOAc (5 mL) followed by EtOH (5 mL) and then 10%aqueous KHSO₄ solution (5 mL). The reaction mixture was stirred at roomtemperature for an additional 10 min, and was then filtered through apad of Celite® filter agent. The Celite® was washed with EtOH (50 mL)and the filtrate was concentrated at reduced pressure. The residue waspurified by MPLC (80:20 CH₂Cl₂/MeOH) to give 3.2 g (79%) of the desiredproduct. ¹H-NMR (DMSO-d₆) δ 9.38 (s, 1H), 8.41 (dd, J=1.5, 4.8 Hz, 2H),7.49 to 7.46 (m, 6H), 7.07 (d, J=6.9 Hz, 2H), 6.85 (dd, J=1.8, 4.8 Hz,2H), 6.32 (s, 1H), 3.82 (s, 2H), 1.26 (s, 9H); MS LC-MS [M+H]⁺=457,RT=1.96 min.

Example 15N-[4-(3-tert-Butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzyl]-2-methoxy-acetamide

To a solution of1-[2-(4-aminomethyl-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea(400 mg, 0.88 mmol) in THF (20 mL) was added N,N-diisopropylethylamine(0.23 mL, 1.31 mmol). A solution of 3-methoxypropionyl chloride (95 mg,0.88 mmol) in THF (1 mL) was added to the solution at 0° C. under N₂ andthe reaction mixture was stirred at room temperature for 3 h. Thereaction mixture was concentrated at reduced pressure and dissolved inEtOAc (100 mL). The solution was washed with water and brine, dried overNa₂SO₄, and concentrated at reduced pressure. The residue was purifiedby MPLC (50:50 hexanes/EtOAc) to give 240 mg (52%) of the desiredproduct. ¹H-NMR (DMSO-d₆) δ 9.16 (s, 1H), 8.42 to 8.40 (m, 4H), 7.50 to7.37 (m, 6H), 7.08 (d, J=8.7 Hz, 2H), 6.85 (d, J=6.0 Hz, 2H), 6.34 (s,1H), 4.33 (d, J=6.0 Hz, 2H), 3.86 (s, 2H), 3.26 (s, 3H), 1.25 (s, 9H);MS LC-MS [M+H]⁺=529, RT=2.29 min.

Example 161-(5-tert-Butyl-2-{4-[(2-methoxy-ethylamino)-methyl]-phenyl}-2H-pyrazol-3-yl)-3-[4-(Pyridin-4-yloxy)phenyl]urea

To a solution ofN-[4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzyl]-2-methoxy-acetamide(200 mg, 0.38 mmol) in anhydrous THF (10 mL) was added borane-methylsulfide complex (2.0 M solution in THF, 1 mL, 2 mmol), and the reactionwas stirred at reflux for 7 h. The reaction mixture was cooled to roomtemperature, partitioned between EtOAc (50 mL) and water (50 mL), andthen the organic layer was separated and washed with brine, dried overNa₂SO₄, and concentrated at reduced pressure. The residue was purifiedby MPLC (90:10 CH₂Cl₂/MeOH) to give 30 mg (15%) of the desired product.¹H-NMR (DMSO-d₆) δ 8.79 (s, 1H), 8.42 (d, J=4.8 Hz, 2H), 7.61 to 7.46(m, 7H), 7.06 (d, J=6.6 Hz, 2H), 6.84 (d, J=4.5 Hz, 2H), 6.44 (s, 1H),3.85 (s, 2H), 3.49 (t, J=5.7 Hz, 2H), 3.29 (s, 3H), 2.81 (t, J=5.7 Hz,2H), 1.31 (s, 9H); MS LC-MS [M+H]⁺=515, RT=2.02 min.

Example 171-[2-(4-{[Bis-(2-hydroxy-ethyl-amino]-methyl}-phenyl)-5-tert-butyl-2H-pyrazo-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]ureaStep 1.1-{2-[4-({bis-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-amino}-methyl)-phenyl]-5-tert-butyl-2H-pyrazo-3-yl}-3-[4-(pyridin-4-yloxy)phenyl]urea

To a solution of1-[2-(4-aminomethyl-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea(200 mg, 0.44 mmol) and sodium triacetoxyborohydride (186 mg, 0.88 mmol)in anhydrous THF (3 mL) was addedtert-butyldimethylsilyloxy)-acetaldahyde (153 mg, 0.88 mmol) and aceticacid (53 mg, 0.88 mmol), and then the reaction mixture was stirred atroom temperature for 2 h. The reaction mixture was partitioned betweenEtOAc (20 mL) and water (10 mL), and the organic layer was washed withbrine, dried over Na₂SO₄, and concentrated at reduced pressure. Theresidue was purified by MPLC (50:50 hexanes/EtOAc) to give 160 mg (47%)of the desired product. ¹H-NMR (DMSO-d₆) δ 8.48 (s, 1H), 8.36 (d, J=4.5Hz, 2H), 7.78 (s, 1H), 7.54 (d, J=6.6 Hz, 2H), 7.53 to 7.40 (m, 4H),7.01 (d, J=6.6 Hz, 2H), 6.79 (d, J=5.7 Hz, 2H), 6.38 (s, 1H), 3.76 (s,2H), 3.70 (t, J=6.3 Hz, 4H), 2.67 (t, J=6.3 Hz, 4H), 1.26 (s, 9H), 0.83(s, 18H), 0.00 (s, 12H); MS LC-MS [M+H]⁺=773, RT=3.39 min.

Step 2.1-[2-(4-{[Bis-(2-hydroxy-ethyl-amino]-methyl}-phenyl)-5-tert-butyl-2H-pyrazo-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea

To a solution of1-{2-[4-({bis-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-amino}-methyl)-phenyl]-5-tert-butyl-2H-pyrazo-3-yl}-3-[4-(pyridin-4-yloxy)phenyl]urea(160 mg, 0.21 mmol) in methanol (5 mL) was added 10% aqueous TFAsolution (5 mL), and then the reaction mixture was stirred at roomtemperature for 4 h. The reaction mixture was partitioned between EtOAc(20 mL) and saturated aq NaHCO₃ (20 mL), and then the organic layer waswashed with brine, dried over Na₂SO₄, and concentrated at reducedpressure. The residue was purified by MPLC (90:10 CH₂Cl₂/MeOH) to give34 mg (30%) of the desired product. ¹H-NMR (DMSO-d₆) δ 9.12 (s, 1H),8.42 to 8.40 (m, 3H), 7.50 to 7.42 (m, 6H), 7.08 (d, J=6.9 Hz, 2H), 6.85(d, J=6.3 Hz, 2H), 6.35 (s, 1H), 4.39 (b, 2H), 3.69 (s, 2H), 3.45 (m,4H), 2.54 (m, 4H), 1.24 (s, 9H); MS LC-MS [M+H]⁺ 545, RT=2.03 min.

Example 182-Amino-N-[4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzyl]-acetamideStep 1.{[4-(3-tert-Butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzylcarbamoyl]-methyl}-carbamicacid tert-butyl ester

To a solution of N-Boc-glycine (260 mg, 1.48 mmol), EDCI (283 mg, 148mmol) and HOBT (200 mg, 1.48 mmol) in THF/acetonitrile (50:50, 5 mL) wasadded N,N-diisopropylethylamine (380 mg, 2.96 mmol), and the resultingreaction mixture was stirred at room temperature for 1 h. Then,1-[2-(4-aminomethyl-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea(450 mg, 0.99 mmol) was added to the solution and the reaction mixturewas stirred at 50° C. for 18 h. The reaction mixture was cooled to roomtemperature, concentrated at reduced pressure, and the residue wasdissolved in EtOAc (20 mL). The solution was washed with water andbrine, dried over Na₂SO₄, and concentrated at reduced pressure. Theresidue was purified by preparative TLC (50:50 hexanes/EtOAc) to give 65mg (11%) of the desired product. ¹H-NMR (DMSO-d₆)

8.68 (s, 1H), 8.42 (d, J=6.3 Hz, 2H), 7.98 (s, 1H), 7.82 (b, 1H), 7.61(d, J=6.9 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.08(d, J=6.6 Hz, 2H), 6.80 (d, J=6.3 Hz, 2H), 6.46 (s, 1H), 4.48 (d, J=6.0Hz, 2H), 3.78 (d, J=5.7 Hz, 2H), 1.35 (s, 9H), 1.30 (s, 9H); MS LC-MS[M+H]⁺=614, RT=2.89 min.

Step 2.2-Amino-N-[4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzyl]-acetamide

To a solution of{[4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzylcarbamoyl]-methyl}-carbamicacid tert-butyl ester (60 mg, 0.10 mmol) in THF (5 mL) was added TFA (3mL), and the resulting mixture was stirred at room temperature for 18 h.The reaction mixture was partitioned between EtOAc (20 mL) and saturatedNaHCO₃ aqueous solution (20 mL), and the organic layer was removed andwashed with brine, dried over Na₂SO₄, and concentrated at reducedpressure. The residue was purified by preparative TLC (90:10CH₂Cl₂/MeOH) to give 10 mg (20%) of the desired product. ¹H-NMR(DMSO-d₆) δ 8.72 (s, 1H), 8.32 (d, J=5.7 Hz, 2H), 8.02 (s, 1H), 7.53 to7.30 (m, 6H), 6.96 (d, J=6.6 Hz, 2H), 6.73 (d, J=6.3 Hz, 2H), 6.32 (s,1H), 4.36 (s, 2H), 3.70 (S, 2H), 1.18 (s, 9H); MS LC-MS [M+H]⁺=513,RT=2.01 min.

Example 193-(3-tert-Butyl-5-{3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-benzamide

A mixture of3-(3-tert-butyl-5-{3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzoicacid (300.0 mg, 0.60 mmol),1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (93.8 mg, 0.71 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (136.6 mg,0.71 mmol), 4-dimethylaminopyridine (87.3 mg, 0.71 mmol) and1-hydroxybenzotriazole (96.6 mg, 0.71 mmol) in THF and DCM was stirredat room temperature overnight. Ethyl acetate and water were added, andthe organic phase was washed with brine, dried over MgSO₄. andevaporated at reduced pressure. HPLC purification (10-90% aqueousacetonitrile) afforded pure title compound (270 mg, 73%). ¹H-NMR(DMSO-d₆) δ 8.93 (s, 1H), 8.88 (s, 1H), 8.72 (t, J=6.07.66 (m, 2H), 8.30(d, J=5.7 Hz), 8.13 (t, J=9.0 Hz, 1H), 7.98 (s, 1H), 7.89 (d, J=9.0 Hz,1H), 7.69 (m, 2H), 7.19 (d, J=14.7 Hz, 1H), 6.96 (d, J=10.2 Hz, 1H),6.76 (s, 1H), 6.72 (d, J=5.7 Hz, 1H), 6.41 (s, 1H), 3.95 (t, J=6.3 Hz,1H), 3.68 (t, J=6.0 Hz, 1H) 3.28-3.45 (m, 2H), 1.314 (s, 3H), 1.27 (s,9H), 1.22 (s, 3H); MS LC-MS [M+H]⁺=617.3, RT=2.54 min.

Example 203-(3-tert-Butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl-benzamide

This compound was prepared in a similar manner as described for3-(3-tert-butyl-5-{3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-benzamide.MS LC-MS [M+H]⁺=585.3, RT=2.59 min.

Example 213-(3-tert-Butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(2,3-dihydroxypropyl)benzamide

A mixture of3-(3-tert-butyl-5-{3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzoicacid (100 mg, 0.20 mmol), 3-aminopropane-1,2-diol (22 mg, 0.24 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (46 mg,0.24 mmol), 4-dimethylaminopyridine (29 mg, 0.24 mmol) and1-hydroxybenzotriazole (32 mg, 0.24 mmol) in THF and DCM was stirred atroom temperature overnight. Ethyl acetate and water were added, and theorganic phase was washed with brine, dried over MgSO₄, and evaporated atreduced pressure. HPLC purification (10-90% aqueous acetonitrile)afforded pure title compound (23 mg, 20%). ¹H-NMR (DMSO-d₆) δ 8.97 (s,1H), 8.91 (s, 1H), 8.55 (t, J=5.7 Hz, 1H), 8.29 (d, J=7.2 Hz, 1H), 8.11(t, J=9.0 Hz, 1H), 7.98 (s, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.64-7.58 (m,2H), 7.18 (d, J=9.0 Hz, 1H), 6.94 (d, J=12.0 Hz, 1H), 6.76 (s, 1H), 4.81(s, 1H), 4.57 (s, 1H), 3.62 (t, J=5.7 Hz, 1H). 3.40 (m, 2H), 3.18 (m,2H), 2.36 (s, 3H), 1.80 (s, 9H), MS LC-MS [M+H]⁺=577.3, RT=1.54 min.

Example 223-(3-tert-Butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-N-(2,3-dihydroxy-propyl)benzamide

To a solution of3-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl-benzamide(120 mg, 0.21 mmol) in acetone, 2N HCl (0.2 mL, 0.4 mmol) was added. Themixture was stirred at room temperature overnight. EtOAc was added, andthe organic layer was washed with brine, dried over MgSO₄, andevaporated at reduced pressure. HPLC purification (10-90% aqacetonitrile) afforded pure title compound (36.5 mg, 33%). ¹H-NMR(DMSO-d₆) δ 9.19 (s, 1H), 8.54 (s, 4H), 7.99 (s, 1H), 7.87 (d, J=10.5Hz, 1H), 7.68-7.49 (m, 4H), 7.15-7.07 (m, 4H), 6.37 (s, 1H), 3.71-3.11(m, 5H), 1.20 (s, 9H); MS LC-MS [M+H]⁺=545.3, RT=2.21 min.

Example 231-[5-tert-Butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-4-(2-methyl-Pyridin-4-yloxy)-phenyl)-urea

To a solution of4-(3-tert-butyl-5-{3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzoicacid methyl ester (700 mg, 1.35 mmol) in anhydrous THF at 0° C. wasslowly added a 1N solution of lithium aluminum hydride in THF (0.95 mL,0.95 mmol). The mixture was stirred at room temperature for 15 minutes,and then water was added dropwise to quench the reaction. The mixturewas extracted with EtOAc, and the combined organic phases were driedover MgSO₄ and evaporated at reduced pressure. The residue was purifiedby HPLC (10% to 90% aq acetonitrile) to afford 600 mg (90%) of the titlecompound as a white solid. ¹H-NMR (DMSO-d₆) δ 8.97 (s, 1H), 8.79 (s,1H), 8.29 (d, J=5.7 Hz, 1H), 8.13 (t, J=9.0 Hz, 1H), 7.46 (m, 4H), 7.18(d, J=14.7 Hz, 1H), 6.95 (d, J=10.2 Hz, 1H), 6.76 (d, J=2.1 Hz, 1H),6.71 (d, J=5.4 Hz, 1H), 6.36 (s, 1H), 5.30 (t, J=5.7 Hz, 2H), 2.38 (s,3H), 1.25 (s, 9H); MS LC-MS [M+H]⁺=490.2, RT=2.41 min.

Example 241-{5-tert-Butyl-2-[4-(2-methoxy-ethoxymethyl)-phenyl]-2H-pyrazol-3-yl}-3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl]-urea

To a solution of1-[5-tert-butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl)-urea(170 mg, 0.35 mmol) in anhydrous THF was added K₂CO₃ (52 mg, 0.38 mmol)followed by methanesulfonyl chloride (30 μL, 0.38 mmol). The mixture wasstirred at room temperature for one day, and then 2-methoxy-ethanol (213mg, 3.5 mmol) was added. The mixture was stirred at room temperatureovernight, then EtOAc was added followed by saturated Na₂CO₃. Theorganic layer was washed with saturated Na₂CO₃ and brine, dried overMgSO₄ and evaporated at reduced pressure. Purification by HPLC (10% to90% aq acetonitrile afforded pure product (10 mg, 5%). ¹H-NMR (CD₃OD) δ8.17 (d, J=6.0 Hz, 1H), 8.01 (t, J=9.3 Hz, 1H), 7.48-7.37 (m, 4H),6.93-6.69 (m, 4H), 6.36 (s, 1H), 4.54 (s, 2H), 3.58 (m, 2H), 3.50 (m,2H), 3.28 (s, 3H), 2.37 (s, 3H), 1.25 (s, 9H); MS LC-MS [M+H]⁺=548.1,RT=2.69 min.

Example 254-(3-tert-Butyl-5-{3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)phenyl]ureido}pyrazol-1-yl)-2-methyl-N-(2-morpholin-4-yl-ethyl)benzene-sulfonamide

To a solution of4-(5-amino-3-tert-butyl-pyrazol-1-yl)-2-methyl-N-(2-morpholin-4-yl-ethyl)benzenesulfonamide(150 mg, 0.36 mmol) in anhydrous DCE (1 mL) was added CDT (64 mg, 0.39mmol, 1.1 eq), and the reaction was stirred under nitrogen at 50° C. for18 h. A solution of 2-fluoro-4-(2-methyl-pyridin-4-yloxy)phenylamine (86mg, 0.39 mmol, 1.1 eq) in anhydrous THF (1 mL) was added to thereaction, and the solution was stirred under at 50° C. for 3 days. Thereaction mixture was partitioned between EtOAc (50 mL) and water (50mL). The organic layer was washed with brine, dried over Na₂SO₄, andconcentrated at reduced pressure. The crude product was purified by HPLCand recrystallized from DCM/hexane to give 55 mg (23%) of the titlecompound as a white solid. ¹H-NMR (DMSO-d₆) δ 8.92 (d, J=14.4 Hz, 2H),8.30 (d, J=5.7 Hz, 1H), 8.07 (t, J=9 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H),7.68 (t, J=6 Hz, 1H), 7.58 to 7.51 (m, 2H), 7.25 (dd, J=11.4, 2.4 Hz,1H), 6.97 to 6.92 (m, 1H), 6.77 (d, J=2.4 Hz, 1H), 6.74 to 6.70 (m, 1H),6.41 (s, 1H), 3.45 (t, J=4.5 Hz, 4H), 2.93 (q, J=6H, 2H), 2.65 (s, 3H),2.39 (s, 3H), 2.25 (t, J=6.9 Hz, 2H), 2.20 to 2.17 (m, 4H), 1.27 (s,9H); MS LC-MS [M+H]⁺=666, RT=2.26 min.

Example 26 Ethyl(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetate

A mixture of ethyl(4-{3-tert-butyl-5-[(phenoxycarbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetate(3.0 g, 7.12 mmol) and 4-(pyridin-4-yloxy)aniline (1.26 g, 6.78 mmol) inTHF (50 mL) was heated at 60° C. overnight. The reaction mixture wascooled to room temperature and then evaporated at reduced pressure toafford a brown syrup, which was purified by MPLC (25:75 to 70:30EtOAc/hexane). The desired product was obtained as a white solid (2.42g) in 70% yield. ¹H-NMR (CD₂Cl₂-d₂) δ 8.35 (m, 2H), 8.06 (s, 1H), 7.42(m, 4H), 7.33 (s, 1H), 7.28 (d, J=8.3 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H),6.88 (d, J=5.8 Hz, 2H), 6.35 (s, 1H), 4.12 (q, J=7.1 Hz, 2H), 3.63 (s,2H), 1.31 (s, 9H), 1.27 (t, J=7.1 Hz, 3H); MS LC-MS [M+H]⁺=514.2,RT=2.66 min.

Example 27(4-[3-tert-Butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino]carbonyl)amino]-1H-pyrazol-1-yl}Phenyl)aceticacid

To a suspension of ethyl(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]-amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetate(2.42 g, 4.72 mmol) in THF/H₂O/EtOH (3:1:1, 50 mL) was added LiOH (0.34g, 14.15 mmol) and the resulting reaction mixture was stirred at roomtemperature for 2.5 h. The mixture was evaporated at reduced pressure toafford a syrup-type residue. The residue was dissolved in 1N HCl, andthen the acidity was adjusted to pH ˜7. The mixture was washed withEtOAc, and then the aqueous phase was acidified to pH 5-6. The whiteprecipitate that formed was collected by filtration, washed with waterand hexane, and air-dried to afford the product as a white solid (2.1 g)in 92% yield. ¹H-NMR (DMSO-d₆) δ 12.45 (broad, 1H), 9.64 (broad, 1H),8.98 (broad, 1H), 8.38 (dd, JJ=1.6 Hz, 4.7 Hz, 2H), 7.51-7.42 (m, 4H),7.36 (d, J=8.3 Hz, 2H), 7.05 (dd, JJ=2.1 Hz, 6.9 Hz, 2H), 6.84 (dd,JJ=1.6 Hz, 4.7 Hz, 2H), 6.31 (s, 1H), 3.58 (s, 2H), 1.27 (s, 9H); MSLC-MS [M+H]⁺=486.2, RT=2.39 min.

Example 28N-[3-tert-butyl-1-[4-(2-hydroxyethyl)phenyl]-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)-phenyl]urea

To a solution of(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}-carbonyl)amino]-1H-pyrazol-1-yl}phenyl)aceticacid (100 mg, 0.21 mmol) in THF (4 mL) was added borane-methyl sulfitecomplex (0.51 mL, 2M in THF) drop-wise with stirring at roomtemperature. The resulting reaction mixture was heated at reflux for 2h, then cooled to room temperature and quenched by the addition ofEtOH/1N HCl. The resulting mixture was heated at reflux for 1 h. Themixture was cooled to room temperature and evaporated at reducedpressure, and the residue was dissolved in a mixture of EtOAc andsaturated NaHCO₃. The organic phase was dried over Na₂SO₄, concentrated,and purified by MPLC (50:50 hexane/EtOAc). The desired product wasobtained as a white solid (50 mg) in 51% yield. ¹H-NMR (DMSO-d₆) δ 9.12(s, 1H), 8.39 (m, 3H), 7.48 (d, J=9.0 Hz, 2H), 7.40-7.33 (m, 4H), 7.07(d, J=8.8 Hz, 2H), 6.85 (m, 2H), 6.34 (s, 1H), 4.69 (t, J=5.1 Hz, 1H),3.64 (m, 2H), 2.78 (t, J=7.1 Hz, 2H), 1.27 (s, 9H); MS LC-MS[M+H]⁺=472.2, RT=2.35 min.

Example 29N-[3-tert-Butyl-1-(4-{2-[(3S)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea

A mixture of(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)-amino]-1H-pyrazol-1-yl}phenyl)aceticacid (150 mg, 0.31 mmol), (S)-3-pyrrolidinol (54 mg, 0.62 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 71mg, 0.37 mmol), 1-hydroxybenzotrazole hydrate (HOBT, 50 mg, 0.37 mmol),and triethylamine (0.09 mL, 0.62 mmol) in THF/CH₂Cl₂ (1/1, 6 mL) wasstirred at room temperature overnight. The mixture was evaporated atreduced pressure, and the residue was dissolved in CH₂Cl₂/MeOH andpurified by MPLC (EtOAc/Hexane/MeOH). ¹H-NMR (DMSO-d₆) δ 9.13 (s, 1H),8.04 (m, 3H), 7.50-7.34 (m, 6H), 7.07 (d, J=8.9 Hz, 2H), 6.85 (dd,JJ=1.8 Hz, 4.8 Hz, 2H), 6.35 (s, 1H), 4.97 (dd, JJ=3.8 Hz, 44.1 Hz, 1H),4.27 (broad d, J=30.7 Hz, 1H), 3.70-3.56 (m, 4H), 3.44-3.27 (m, 2H),1.95-1.73 (m, 2H), 1.27 (s, 9H); MS LC-MS [M+H]⁺=555.2, RT=2.28 min.

Example 30N-[3-tert-Butyl-1-(4-{2-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea

The title compound was prepared in the same manner as described forN-{3-tert-butyl-1-[4-(2-hydroxyethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]-urea,replacing(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)aceticacid withN-[3-tert-butyl-1-(4-{2-[(3S)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea(90 mg, 0.16 mmol). The title compound was purified by HPLC, the TFAsalt isolated from HPLC was neutralized, and the title compound wasobtained as a white solid (25 mg) in 29% yield. ¹H-NMR (DMSO-d₆) δ 9.11(broad, 1H), 8.39 (m, 3H), 7.47 (d, J=8.8 Hz, 2H), 7.37 (m, 4H), 7.07(d, J=8.9 Hz, 2H), 6.84 (m, 2H), 6.34 (s, 1H), 4.67 (d, J=4.5 Hz, 1H),4.16 (broad, 1H), 2.76 (m, 2H), 2.61 (m, 2H), 2.48 (m, 1H), 2.34 (m,1H), 1.96 (broad, 1H), 1.52 (broad, 1H); MS LC-MS [M+H]⁺=541.2, RT=2.04min.

Example 31 MethylN-[(4-[3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl]phenyl)acetyl]-L-serinate

The title compound was prepared in the same manner as described forN-[3-tert-butyl-1-(4-{2-[(3S)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea,replacing (S)-3-pyrrolidinol with L-serine methyl ester hydrochloride.The desired product was purified by MPLC (EtOAc/hexane/MeOH) andobtained as a solid (150 mg) in 62% yield. A sample of this material waspurified further by HPLC and the TFA salt isolated from HPLC wasneutralized to provide the title compound. ¹H-NMR (DMSO-d₆) δ9.12 (s,1H), 8.50 (d, J=7.9 Hz, 1H) 8.40 (m, 3H), 7.50-7.38 (m, 6H), 7.07 (d,J=8.7 Hz, 2H), 6.85 (m, 2H), 6.34 (s, 1H), 5.10 (t, J=5.4 Hz, 1H), 4.35(m, 1H), 3.72 (m, 1H), 3.61 (m, 6H), 1.27 (s, 9H); MS LC-MS[M+H]⁺=587.2, RT=2.27 min.

Example 32N-[(4-{3-tert-Butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl]amino]-1H-pyrazol-1-yl}phenyl)acetyl]-L-serine

The title compound was prepared in the same manner as described for(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-aceticacid. The title compound was obtained as a pale solid in 78% yield.¹H-NMR (DMSO-d₆) δ 12.59 (broad, 1H), 9.15 (s, 1H), 8.40 (m, 2H), 8.34(d, J=7.6 Hz, 1H), 7.48 (d, J=9.0 Hz, 2H), 7.41 (s, 4H), 7.07 (d, J=8.9Hz, 2H), 6.85 (m, 2H), 6.35 (s, 1H), 5.05 (broad, 1H), 4.27 (m, 1H),3.70 (m, 1H), 3.61 (m, 3H), 1.27 (s, 9H); MS LC-MS [M+H]⁺=573.1, RT=2.22min.

Example 332-(4-{3-tert-Butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-N-[2-hydroxy-1-(hydroxymethyl)ethyl]acetamide

The title compound was prepared in the same manner as described forN-[3-tert-butyl-1-(4-{2-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea,and was obtained as a white solid in 24% yield. ¹H-NMR (DMSO-d₆) δ 9.11(s, 1H), 8.39 (m, 3H), 7.48 (d, J=9.0 Hz, 2H), 7.38 (m, 4H), 7.07 (d,J=9.2 Hz, 2H), 6.85 (m, 2H), 6.34 (s, 1H), 4.38 (t, J=5.4 Hz, 2H),3.40-3.27 (m, 4H), 2.84 (m, 2H), 2.75 (m, 2H), 2.54 (m, 1H), 1.60(broad, 1H), 1.27 (s, 9H); MS LC-MS [M+H]⁺=545.3, RT=2.14 min.

Biological Assay Examples Flk-1 (Murine VEGFR-2) Biochemical Assay

This assay was performed in 96-well opaque plates (Costar 3915) in theTR-FRET format. Reaction conditions are as follows: 10 μM ATP, 25 nMpoly GT-biotin, 2 nM Eu-labelled phospho-Tyr Ab (PY20 Perkin Elmer), 10nM APC (Perkin Elmer), 7 nM Flk-1 (kinase domain), 1% DMSO, 50 mM HEPESpH 7.5, 10 mM MgCl₂, 0.1 mM EDTA, 0.015% BRIJ, 0.1 mg/mL BSA, 0.1%mercapto-ethanol). Reaction is initiated upon addition of enzyme. Finalreaction volume in each well is 100 μL. Plates are read at both 615 and665 nM on a Perkin Elmer Victor V Multilabel counter at about 1.5-2.0hours after reaction initiation. Signal is calculated as a ratio: (665nm/615 nm)*10000 for each well.

The compounds of Formula I tested in this VEGFR2 kinase assay showedsignificant inhibitory activity (IC₅₀<10 μM). The compounds of Examples1 to 33 showed inhibition of VEGFR2 kinase activity in this assay withIC₅₀<300 nM.

Trk-A FRET Biochemical Assay

This assay uses the N-terminal HIS-tagged intracellular kinase domain ofhuman recombinant Trk-A in 96-well plates. This involves abiotinylated-poly-GluTyr substrate and an Eu-labelledanti-phosphotyrosine antibody for detection of kinase activity in ahomogeneous time-resolved FRET format. The Trk-A biochemical FRET assayprotocol is as follows: 10 mM stock solution of test compounds arediluted to 1 mM in 100% DMSO. These stocks are diluted with 100% DMSO bya factor of 5, in a total of 7 steps to create an 8-point IC₅₀ curve.The diluted compounds are combined 1:4 with distilled water to form the25× dilution plate for the assay.

A 2 μL aliquot of compound from the 25× dilution plate is added with 23μL of assay buffer (50 mM HEPES pH 7.0, 5 mM MnCl₂, 0.1% BSA, 0.5 mMvanadate, 0.1% β-mercaptoethanol) into a 96-well, half volume opaque(black) plate (Costar #3694). ATP is added to all wells except thenegative controls (5 microliters of 40 μM). Five microliters of 2.2μg/mL poly(GluTyr)-biotin (CIS US # 61GT0BLB) and 15 μL of 6.66 nM Trk-Adiluted in assay buffer are added to the plate to start the reaction.

After 60 min. at room temperature, the assay is stopped with addition of5 μL of 0.5M EDTA. 25 μL each of 340 ng/mL PY20 cryptate antibody (CISUS #61Y20KLA) and 40 nM streptavidin labelled APC (SA-XL-CIS US # 611SAXLB) are added in development buffer (50 mM HEPES pH7.0, 0.8M KF, 0.1%BSA). The assay plate sits at room temperature for at least one hour,then is read on a Perkin Elmer Victor 2 instrument at 615 and 665 nMemission. A ratio of these two numbers is used in the calculations ofthe data.

The compounds of Examples 1 to 243 showed significant inhibition ofTrk-A kinase activity in this assay (IC₅₀<1 μM). The compounds ofExamples 1 to 33 showed inhibition of Trk-A kinase activity in thisassay with IC₅₀<200 nM.

It is believed that one skilled in the art, using the precedinginformation and information available in the art, can utilize thepresent invention to its fullest extent. It should be apparent to one ofordinary skill in the art that changes and modifications can be made tothis invention without departing from the spirit or scope of theinvention as it is set forth herein. The topic headings set forth aboveand below are meant as guidance where certain information can be foundin the application, but are not intended to be the only source in theapplication where information on such topic can be found.

All publications and patents cited above are incorporated herein byreference.

Additional compounds as listed below and illustrated in Table 1 wereprepared as described above by choosing the appropriate startingmaterials or intermediates, and using the processes described as inExamples 1 to 33 or other standard chemical processes known in the art.

-   1.    4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-pyrrolidin-1-ylethyl)benzamide-   2.    N-{3-tert-butyl-1-[4-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   3.    N-{3-tert-butyl-1-[4-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   4.    N-(3-tert-butyl-1-{4-[2-(diethylamino)ethoxy]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea-   5.    N-{3-tert-butyl-1-[4-(2-piperidin-4-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea-   6.    N-{3-tert-butyl-1-[3-(3-hydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   7.    N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-3-methoxypropanamide-   8.    N-(3-tert-butyl-1-{4-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea-   9.    4-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-2,2-dimethyl-4-oxobutanoic    acid-   10.    N-(3-tert-butyl-1-{4-[(4-hydroxy-3,3-dimethylbutyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea-   11.    N-(3-tert-butyl-1-{3-[(3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea-   12.    N-(3-tert-butyl-1-{3-[[(dimethylamino)sulfonyl](3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea-   13.    N-(1-{3-[bis(2-hydroxyethyl)amino]phenyl}-3-tert-butyl-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea-   14.    N-{1-[4-(aminomethyl)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)-phenyl]urea-   15.    N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)-2-methoxyacetamide-   16.    N-[3-tert-butyl-1-(4-{[(2-methoxyethyl)amino]methyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea-   17.    N-[1-(4-{[bis(2-hydroxyethyl)amino]methyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea-   18.    N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)glycinamide-   19.    3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy}phenyl]amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]benzamide-   20.    3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]benzamide-   21.    3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-(2,3-dihydroxypropyl)benzamide-   22.    3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2,3-dihydroxypropyl)benzamide-   23.    N-{3-tert-butyl-1-[4-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   24.    N-(3-tert-butyl-1-{4-[(2-methoxyethoxy)methyl]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   25.    4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-2-methyl-N-(2-morpholin-4-ylethyl)benzenesulfonamide-   26.    ethyl(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetate-   27.    (4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetic    acid-   28.    N-{3-tert-butyl-1-[4-(2-hydroxyethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   29.    N-[3-tert-butyl-1-(4-{2-[(3S)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea-   30.    N-[3-tert-butyl-1-(4-{2-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea-   31. methyl    N-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetyl]-L-serinate-   32.    N-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetyl]-L-serine-   33.    N-{3-tert-butyl-1-[4-(2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}ethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   34.    N-{3-tert-butyl-1-[4-(2-piperidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   35.    N-{3-tert-butyl-1-[4-(2-morpholin-4-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   36.    N-{3-tert-butyl-1-[4-(3-morpholin-4-ylpropoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   37.    N-{3-tert-butyl-1-[4-(3-morpholin-4-ylpropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   38.    N-{3-tert-butyl-1-[4-(3-morpholin-4-ylpropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea-   39.    N-{3-tert-butyl-1-[4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   40.    N-{3-tert-butyl-1-[4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea-   41.    N-{3-tert-butyl-1-[4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   42.    N-{3-tert-butyl-1-[4-(3-hydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   43.    N-{3-tert-butyl-1-[4-(3-hydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea-   44.    N-{3-tert-butyl-1-[4-(3-hydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   45.    N-{3-tert-butyl-1-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   46.    N-{3-tert-butyl-1-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea-   47.    N-{3-tert-butyl-1-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   48.    tert-butyl-4-{2-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}-amino)carbonyl]amino}-1H-pyrazol-1-yl)phenoxy]ethyl}piperidine-1-carboxylate-   49.    N-{3-tert-butyl-1-[4-(2-piperidin-4-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   50.    butyl-4-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenoxy)butanoate-   51.    butyl-4-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)phenoxy]butanoate-   52. tert-butyl    {2-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)phenoxy]ethyl}carbamate-   53.    N-{1-[4-(2-aminoethoxy)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   54.4-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)phenoxy]butanoic    acid-   55.    4-(4-{(3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenoxy)butanoic    acid-   56. tert-butyl    4-[2-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenoxy)ethyl]piperidine-1-carboxylate-   57.    N-{3-tert-butyl-1-[4-(2-piperidin-4-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   58. tert-butyl    4-[2-(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenoxy)ethyl]piperidine-1-carboxylate-   59. tert-butyl    [2-(4-{(3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenoxy)ethyl]carbamate-   60.    N-{1-[4-(2-aminoethoxy)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)-phenyl]urea-   61. tert-butyl    [2-(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenoxy)ethyl]carbamate-   62.    N-{1-[4-(2-aminoethoxy)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)-phenyl]urea-   63.    N-{3-tert-butyl-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   64.    N-{3-tert-butyl-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   65.    N-{3-tert-butyl-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea-   66.    N-{3-tert-butyl-1-[4-(2,3-dihydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   67.    N-{3-tert-butyl-1-[4-(2,3-dihydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   68.    N-{3-tert-butyl-1-[3-(3-morpholin-4-ylpropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   69.    N-{3-tert-butyl-1-[3-(3-morpholin-4-ylpropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea-   70.    N-{3-tert-butyl-1-[3-(3-morpholin-4-ylpropoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   71.    N-{3-tert-butyl-1-[3-(3-hydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   72.    N-{3-tert-butyl-1-[3-(3-hydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea-   73.    N-{3-tert-butyl-1-[3-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   74.    N-{3-tert-butyl-1-[3-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea-   75.    N-{3-tert-butyl-1-[3-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   76.    N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)phenyl]-3-methoxypropanamide-   77.    N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-methoxyacetamide-   78.    N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)phenyl]-2-methoxyacetamide-   79.2-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-2-oxoethyl    acetate-   80.    2-bromo-N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetamide-   81.    N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}-carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-morpholin-4-ylacetamide-   82.    N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-pyrrolidin-1-ylacetamide-   83.    N-(3-tert-butyl-1-{4-[(2-morpholin-4-ylethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea-   84.    N-(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-methoxyacetamide-   85.    N-(3-tert-butyl-1-{4-[(2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea-   86.    N-(3-tert-butyl-1-{4-[(2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-3-yloxy)phenyl]urea-   87.    N-(3-tert-butyl-1-{4-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-3-yloxy)phenyl]urea-   88.    N-(3-tert-butyl-1-{4-[(3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea-   89.    N-(3-tert-butyl-1-{4-[(3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-3-yloxy)phenyl]urea-   90.4-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-4-oxobutanoic    acid-   91.    4-[(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-4-oxobutanoic    acid-   92.    4-[(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-2,2-dimethyl-4-oxobutanoic    acid-   93.    N-(3-tert-butyl-1-{4-[(2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   94.    N-(3-tert-butyl-1-{4-[(3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   95.    N-(3-tert-butyl-1-{4-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   96.    N-(3-tert-butyl-1-{4-[[(dimethylamino)sulfonyl](2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea-   97.    N-(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-methoxyacetamide-   98.    N-(3-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-methoxyacetamide-   99.    N-(3-tert-butyl-1-{3-[(2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea-   100.    N-(3-tert-butyl-1-{3-[(2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-3-yloxy)phenyl]urea-   101.    N-(3-tert-butyl-1-{3-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea-   102.    N-(3-tert-butyl-1-{3-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-3-yloxy)phenyl]urea-   103.    N-(3-tert-butyl-1-{3-[(3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-3-yloxy)phenyl]urea-   104.    4-[(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-4-oxobutanoic    acid-   105.    4-[(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-2,2-dimethyl-4-oxobutanoic    acid-   106.    4-[(3-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-4-oxobutanoic    acid-   107.    4-[(3-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-2,2-dimethyl-4-oxobutanoic    acid-   108.    N-[3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)phenyl]-2-methoxyacetamide-   109.    N-(3-tert-butyl-1-{3-[(2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   110.    N-(3-tert-butyl-1-{3-[(3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   111.    N-(3-tert-butyl-1-{3-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   112.    N-(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-morpholin-4-ylacetamide-   113.    N-(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-(1H-imidazol-1-yl)acetamide-   114.    N-(3-tert-butyl-1-{3-[[(dimethylamino)sulfonyl](2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea-   115.    N-(3-tert-butyl-1-{3-[(2-morpholin-4-ylethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea-   116.    4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-methoxyethyl)benzamide-   117.    4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-methoxyethyl)-N-methylbenzamide-   118.    4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-methyl-N-[2-(methylsulfonyl)ethyl]benzamide-   119.    4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(4-pyrrolidin-1-ylbutyl)benzamide-   120.    4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-morpholin-4-ylethyl)benzamide-   121.    4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[3-(diethylamino)propyl]benzamide-   122.    4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(dimethylamino)ethyl]benzamide-   123.    4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(3-pyrrolidin-1-ylpropyl)benzamide-   124.    4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(1H-pyrazol-1-yl)ethyl]benzamide-   125.    4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[3-(1H-imidazol-1-yl)propyl]benzamide-   126.    4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-(4-pyrrolidin-1-ylbutyl)benzamide-   127.    4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-[3-(diethylamino)propyl]benzamide-   128.    4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-(2-morpholin-4-ylethyl)benzamide-   129.    4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)-N-(2-pyrrolidin-1-ylethyl)benzamide-   130.    4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[3-(diethylamino)propyl]benzamide-   131.    4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-morpholin-4-ylethyl)benzamide-   132.    4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(4-pyrrolidin-1-ylbutyl)benzamide-   133.    4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-pyrrolidin-1-ylethyl)benzamide-   134.    4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(dimethylamino)ethyl]benzamide-   135.    4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-methyl-N-[2-(methylsulfonyl)ethyl]benzamide-   136.    3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-pyrrolidin-1-ylethyl)benzamide-   137.    3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[3-(diethylamino)propyl]benzamide-   138.    3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-methoxyethyl)benzamide-   139.    3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(tetrahydrofuran-2-ylmethyl)benzamide-   140.    3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}benzamide-   141.    N-[2-(acetylamino)ethyl]-3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}-carbonyl)amino]-1H-pyrazol-1-yl}benzamide-   142.    3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[3-(1H-imidazol-1-yl)propyl]benzamide-   143.    3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(2-hydroxyethoxy)ethyl]benzamide-   144.    3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(1-methylpyrrolidin-2-yl)ethyl]benzamide-   145.    3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(3-hydroxy-2,2-dimethylpropyl)benzamide-   146. tert-butyl    4-{[(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)-amino]-1H-pyrazol-1-yl}benzoyl)amino]methyl}piperidine-1-carboxylate-   147.    3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(piperidin-4-ylmethyl)benzamide-   148.    3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(3-hydroxypropyl)benzamide-   149.    3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-(3-hydroxypropyl)benzamide-   150.    3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-(2-hydroxyethyl)benzamide-   151.    3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-hydroxyethyl)benzamide-   152.    N-[2-(acetylamino)ethyl]-3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzamide-   153.    3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-[3-(1H-imidazol-1-yl)propyl]benzamide-   154.    3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-(tetrahydrofuran-2-ylmethyl)benzamide-   155.    3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)-N-(2-pyridin-4-ylethyl)benzamide-   156.    3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)-N-[3-(diethylamino)propyl]benzamide-   157.    3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]benzamide-   158.    3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-(2-pyrrolidin-1-ylethyl)benzamide-   159.    3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-(4-pyrrolidin-1-ylbutyl)benzamide-   160.    3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-(3-hydroxy-2,2-dimethylpropyl)benzamide-   161. tert-butyl    4-({[3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}-amino)carbonyl]amino}-1H-pyrazol-1-yl)benzoyl]amino}methyl)piperidine-1-carboxylate-   162.    3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-(piperidin-4-ylmethyl)benzamide-   163.    4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(tetrahydrofuran-2-ylmethyl)benzenesulfonamide-   164.    4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-morpholin-4-ylethyl)benzenesulfonamide-   165.    4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-(2-morpholin-4-ylethyl)benzenesulfonamide-   166.    4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]benzenesulfonamide-   167.    4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(1-methylpyrrolidin-2-yl)ethyl]benzenesulfonamide-   168.    4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-2-methyl-N-(2-morpholin-4-ylethyl)benzenesulfonamide-   169.    4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(tetrahydrofuran-2-ylmethyl)-2-(trifluoromethoxy)benzenesulfonamide-   170.    4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-(tetrahydrofuran-2-ylmethyl)-2-(trifluoromethoxy)-benzenesulfonamide-   171.    4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-2-methyl-N-(tetrahydrofuran-2-ylmethyl)benzenesulfonamide-   172.    4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-2-methyl-N-(tetrahydrofuran-2-ylmethyl)-benzenesulfonamide-   173.    4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(tetrahydrofuran-2-ylmethyl)benzenesulfonamide-   174.    3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-methoxyethyl)benzenesulfonamide-   175.    3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-(2-methoxyethyl)benzenesulfonamide-   176.    3-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-methoxyethyl)benzenesulfonamide-   177.    3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(dimethylamino)ethyl]benzenesulfonamide-   178.    3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)-N-[2-(dimethylamino)ethyl]benzenesulfonamide-   179.    N-{1-[4-(aminomethyl)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)-phenyl]urea-   180.    N-(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)-2-methoxyacetamide-   181.    N-{1-[4-(aminomethyl)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   182.    N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)benzyl]-2-methoxyacetamide-   183.    N-[3-tert-butyl-1-(4-{[(2-methoxyethyl)amino]methyl}phenyl)-1H-pyrazol-5-yl]-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   184.    N-[1-(4-{[bis(2-hydroxyethyl)amino]methyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-N′-[4-(pyridin-3-yloxy)phenyl]urea-   185.    N-[1-(4-{[bis(2-hydroxyethyl)amino]methyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   186.    N-[1-(4-{[bis(3-hydroxypropyl)amino]methyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea-   187.    N-[1-(4-{[bis(3-hydroxypropyl)amino]methyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-N′-[4-(pyridin-3-yloxy)phenyl]urea-   188.    N-[1-(4-{[bis(3-hydroxypropyl)amino]methyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   189.    N2-acetyl-N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)-amino]-1H-pyrazol-1-yl}benzyl)glycinamide-   190.    tert-butyl{2-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)amino]-2-oxoethyl}carbamate-   191.    tert-butyl{2-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)amino]-1-methyl-2-oxoethyl}carbamate-   192.    N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)-2-(1-methyl-1H-imidazol-4-yl)acetamide-   193.    N-(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)glycinamide-   194.    N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)benzyl]acetamide-   195.    N2-acetyl-N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}-amino)carbonyl]amino}-1H-pyrazol-1-yl)benzyl]glycinamide-   196.    tert-butyl(2-{[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}-amino)carbonyl]amino}-1H-pyrazol-1-yl)benzyl]amino}-2-oxoethyl)carbamate-   197.    tert-butyl(2-{[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}-amino)carbonyl]amino}-1H-pyrazol-1-yl)benzyl]amino}-1-methyl-2-oxoethyl)carbamate-   198.    N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)benzyl]-2-(1-methyl-1H-imidazol-4-yl)acetamide-   199.    N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)benzyl]-1-methyl-1H-imidazole-4-carboxamide-   200.    N2-acetyl-N-(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)-amino]-1H-pyrazol-1-yl}benzyl)glycinamide-   201. tert-butyl    {2-[(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)-amino]-1H-pyrazol-1-yl}benzyl)amino]-2-oxoethyl}carbamate-   202.    N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)benzyl]alaninamide-   203.    N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)benzyl]glycinamide-   204.    N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)alaninamide-   205.    N-[3-tert-butyl-1-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea-   206.    N-{1-[3-(aminomethyl)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   207.    N-{1-[3-(aminomethyl)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   208.    N-(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)acetamide-   209.    N-[3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)benzyl]acetamide-   210.    N2-acetyl-N-(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)-amino]-1H-pyrazol-1-yl}benzyl)glycinamide-   211.    N-(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)-2-methoxyacetamide-   212.    N2-acetyl-N-[3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}-amino)carbonyl]amino}-1H-pyrazol-1-yl)benzyl]glycinamide-   213.    N-[3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)benzyl]-2-methoxyacetamide-   214.    N-[3-tert-butyl-1-(3-{[(2,3-dihydroxypropyl)amino]methyl}phenyl)-1H-pyrazol-5-yl]-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   215.    N-{3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   216.    N-(3-tert-butyl-1-{4-[(2-morpholin-4-ylethoxy)methyl]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   217.    N-{3-tert-butyl-1-[4-(methoxymethyl)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   218.    N-(3-tert-butyl-1-{4-[(2-morpholin-4-ylethoxy)methyl]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   219.    N-{3-tert-butyl-1-[4-(methoxymethyl)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   220.    N-(3-tert-butyl-1-{4-[(2-methoxyethoxy)methyl]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   221.    ethyl[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)phenyl]acetate-   222.    [4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)phenyl]acetic    acid-   223.    N-{3-tert-butyl-1-[4-(2-hydroxyethyl)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea-   224.    N-{3-tert-butyl-1-[4-(2-morpholin-4-yl-2-oxoethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   225.    N-{3-tert-butyl-1-[4-(2-oxo-2-pyrrolidin-1-ylethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   226. tert-butyl    4-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetyl]piperazine-1-carboxylate-   227.    N-(3-tert-butyl-1-{4-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea-   228.    2-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]acetamide-   229.    2-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-N-(2-methoxyethyl)acetamide-   230.    2-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-N-(2-morpholin-4-ylethyl)acetamide-   231.    N-[3-tert-butyl-1-(4-{2-[(3R)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea-   232.    N-{3-tert-butyl-1-[4-(2-morpholin-4-ylethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   233.    N-{3-tert-butyl-1-[4-(2-pyrrolidin-1-ylethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   234.    2-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-N-(2-hydroxyethyl)acetamide-   235.    N-[3-tert-butyl-1-(4-{2-[(2-hydroxyethyl)amino]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea-   236.    N-{3-tert-butyl-1-[4-(2-oxo-2-piperazin-1-ylethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   237.    N-[3-tert-butyl-1-(4-{2-[(3R)-3-hydroxypyrrolidin-1-yl]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea-   238.    N-{3-tert-butyl-1-[4-(2-piperazin-1-ylethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea-   239.    2-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-N-(2,3-dihydroxypropyl)acetamide-   240.    N-[3-tert-butyl-1-(4-{2-[(2,3-dihydroxypropyl)amino]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea-   241.    N-[3-tert-butyl-1-(4-{2-[(2-methoxyethyl)amino]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea-   242.    N-(3-tert-butyl-1-{4-[2-(4-methylpiperazin-1-yl)ethyl]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea-   243.    N-[3-tert-butyl-1-(4-{2-[(2-morpholin-4-ylethyl)amino]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea

LC-MS Ret. Ex. m/z time No. Structure IUPAC name (MH+) (min) 1

4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-pyrrolidin-1-ylethyl)benzamide568 2.48 2

N-{3-tert-butyl-1-[4-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea502 2.84 3

N-{3-tert-butyl-1-[4-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea534 2.39 4

N-(3-tert-butyl-1-{4-[2-(diethylamino)ethoxy]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea543 2.16 5

N-{3-tert-butyl-1-[4-(2-piperidin-4-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea555 2.73 6

N-{3-tert-butyl-1-[3-(3-hydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea502 2.36 7

N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-3-methoxypropanamide529 2.20 8

N-(3-tert-butyl-1-{4-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea501 2.39 9

4-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-2,2-dimethyl-4-oxobutanoicacid 571 2.49 10

N-(3-tert-butyl-1-{4-[(4-hydroxy-3,3-dimethylbutyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea543 2.31 11

N-(3-tert-butyl-1-{3-[(3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea501 2.29 12

N-(3-tert-butyl-1-{3-[[(dimethylamino)sulfonyl](3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea608 2.45 13

N-(1-{3-[bis(2-hydroxyethyl)amino]phenyl}-3-tert-butyl-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea531 2.27 14

N-{1-[4-(aminomethyl)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea457 1.96 15

N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)-2-methoxyacetamide529 2.29 16

N-[3-tert-butyl-1-(4-{[(2-methoxyethyl)amino]methyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea515 2.02 17

N-[1-(4-{[bis(2-hydroxyethyl)amino]methyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea545 2.03 18

N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)glycinamide514 2.01 19

3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]benzamide617 2.54 20

3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]benzamide585 2.59 21

3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(2,3-dihydroxypropyl)benzamide577 1.54 22

3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2,3-dihydroxypropyl)benzamide545 2.21 23

N-{3-tert-butyl-1-[4-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea490 2.41 24

N-(3-tert-butyl-1-{4-[(2-methoxyethoxy)methyl]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea548 2.69 25

4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-2-methyl-N-(2-morpholin-4-ylethyl)benzenesulfonamide666 2.26 26

ethyl(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetate514 2.66 27

(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)aceticacid 486 2.39 28

N-{3-tert-butyl-1-[4-(2-hydroxyethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea472 2.36 29

N-[3-tert-butyl-1-(4-{2-[(3S)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea555 2.28 30

N-[3-tert-butyl-1-(4-{2-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea541 2.04 31

methylN-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetyl]-L-serinate587 2.27 32

N-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetyl]-L-serine573 2.22 33

N-{3-tert-butyl-1-[4-(2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}ethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea545 2.14 34

N-{3-tert-butyl-1-[4-(2-piperidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea555 1.78 35

N-{3-tert-butyl-1-[4-(2-morpholin-4-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea557 1.97 36

N-{3-tert-butyl-1-[4-(3-morpholin-4-ylpropoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea603 2.12 37

N-{3-tert-butyl-1-[4-(3-morpholin-4-ylpropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea571 2.47 38

N-{3-tert-butyl-1-[4-(3-morpholin-4-ylpropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea571 2.73 39

N-{3-tert-butyl-1-[4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea542 2.57 40

N-{3-tert-butyl-1-[4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea 0 2.87 41

N-{3-tert-butyl-1-[4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea574 2.67 42

N-{3-tert-butyl-1-[4-(3-hydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea534 2.85 43

N-{3-tert-butyl-1-[4-(3-hydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea502 2.88 44

N-{3-tert-butyl-1-[4-(3-hydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea502 2.53 45

N-{3-tert-butyl-1-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea541 2.52 46

N-{3-tert-butyl-1-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea541 2.68 47

N-{3-tert-butyl-1-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea573 2.57 48

tert-butyl4-{2-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)phenoxy]ethyl}piperidine-1-carboxylate687 3.24 49

N-{3-tert-butyl-1-[4-(2-piperidin-4-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methyl-pyridin-4-yl)oxy]phenyl}urea587 2.74 50

butyl4-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenoxy)butanoate586 3.40 51

butyl4-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)phenoxy]butanoate618 3.42 52

tert-butyl{2-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)phenoxy]ethyl}carbamate619 3.20 53

N-{1-[4-(2-aminoethoxy)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea519 0.36 54

4-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)phenoxy]butanoicacid 562 2.95 55

4-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenoxy)butanoicacid 530 2.51 56

tert-butyl4-[2-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenoxy)ethyl]piperidine-1-carboxylate655 3.48 57

N-{3-tert-butyl-1-[4-(2-piperidin-4-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea555 2.28 58

tert-butyl4-[2-(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenoxy)ethyl]piperidine-1-carboxylate655 3.51 59

tert-butyl[2-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenoxy)ethyl]carbamate587 3.13 60

N-{1-[4-(2-aminoethoxy)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea487 2.12 61

tert-butyl[2-(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenoxy)ethyl]carbamate587 3.31 62

N-{1-[4-(2-aminoethoxy)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea487 2.25 63

N-{3-tert-butyl-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureatrifluoroacetate(salt) 488 2.29 64

N-{3-tert-butyl-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureatrifluoroacetate (salt) 520 2.80 65

N-{3-tert-butyl-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]ureatrifluoroacetate(salt) 488 2.49 66

N-{3-tert-butyl-1-[4-(2,3-dihydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureatrifluoroacetate(salt) 518 2.30 67

N-{3-tert-butyl-1-[4-(2,3-dihydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureatrifluoroacetate (salt) 550 2.47 68

N-{3-tert-butyl-1-[3-(3-morpholin-4-ylpropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea571 2.53 69

N-{3-tert-butyl-1-[3-(3-morpholin-4-ylpropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea571 2.32 70

N-{3-tert-butyl-1-[3-(3-morpholin-4-ylpropoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea603 2.21 71

N-{3-tert-butyl-1-[3-(3-hydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea534 2.43 72

N-{3-tert-butyl-1-[3-(3-hydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea502 2.91 73

N-{3-tert-butyl-1-[3-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(4-methylpyridin-4-yl)oxy]phenyl}urea573 2.12 74

N-{3-tert-butyl-1-[3-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea541 2.24 75

N-{3-tert-butyl-1-[3-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea541 2.06 76

N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)phenyl]-3-methoxypropanamide561 2.27 77

N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-methoxyacetamide515 2.28 78

N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)phenyl]-2-methoxyacetamide547 1.65 79

2-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-2-oxoethylacetate543 2.78 80

2-bromo-N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetamide563 2.13 81

N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl-2-morpholin-4-ylacetamide570 1.96 82

N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-pyrrolidin-1-ylacetamide554 1.91 83

N-(3-tert-butyl-1-{4-[(2-morpholin-4-ylethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea556 1.53 84

N-(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-methoxyacetamide515 2.56 85

N-(3-tert-butyl-1-{4-[(2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea487 2.22 86

N-(3-tert-butyl-1-{4-[(2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-3-yloxy)phenyl]urea487 2.44 87

N-(3-tert-butyl-1-{4-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-3-yloxy)phenyl]urea501 2.61 88

N-(3-tert-butyl-1-{4-[(3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea501 2.26 89

N-(3-tert-butyl-1-{4-[(3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-3-yloxy)phenyl]urea501 2.45 90

4-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-4-oxobutanoicacid543 2.37 91

4-[(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-4-oxobutanoicacid543 2.53 92

4-[(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-2,2-dimethyl-4-oxobutanoicacid 571 2.65 93

N-(3-tert-butyl-1-{4-[(2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea519 1.69 94

N-(3-tert-butyl-1-{4-[(3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea533 2.30 95

N-(3-tert-butyl-1-{4-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea533 2.46 96

N-(3-tert-butyl-1-{4-[[(dimethylamino)sulfonyl](2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea594 2.40 97

N-(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-methoxyacetamide515 2.42 98

N-(3-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-methoxyacetamide515 2.59 99

N-(3-tert-butyl-1-{3-[(2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea487 2.30 100

N-(3-tert-butyl-1-{3-[(2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-3-yloxy)phenyl]urea487 2.49 101

N-(3-tert-butyl-1-{3-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea501 2.46 102

N-(3-tert-butyl-1-{3-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-3-yloxy)phenyl]urea501 2.70 103

N-(3-tert-butyl-1-{3-[(3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-3-yloxy)phenyl]urea501 2.48 104

4-[(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-4-oxobutanoicacid543 2.32 105

4-[(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-2,2-dimethyl-4-oxobutanoicacid 571 2.48 106

4-[(3-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-4-oxobutanoicacid543 2.54 107

4-[(3-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-2,2-dimethyl-4-oxobutanoicacid 571 2.71 108

N-[3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)phenyl]-2-methoxyacetamide547 2.55 109

N-(3-tert-butyl-1-{3-[(2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea519 1.80 110

N-(3-tert-butyl-1-{3-[(3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea533 2.35 111

N-(3-tert-butyl-1-{3-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea533 2.51 112

N-(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-morpholin-4-ylacetamide570 2.11 113

N-(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-(1H-imidazol-1-yl)acetamide551 2.08 114

N-(3-tert-butyl-1-{3-[[(dimethylamino)sulfonyl](2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea594 2.42 115

N-(3-tert-butyl-1-{3-[(2-morpholin-4-ylethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea556 2.07 116

4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-methoxyethyl)benzamide529 2.17 117

4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-methoxyethyl)-N-methylbenzamide543 2.25 118

4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-methyl-N-[2-(methylsulfonyl)ethyl]benzamide591 2.08 119

4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(4-pyrrolidin-1-ylbutyl)benzamide586 2.05 120

4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-morpholin-4-ylethyl)benzamide584 2.03 121

4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[3-(diethylamino)propyl]benzamide584 1.17 122

4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(dimethylamino)ethyl]benzamide542 1.89 123

4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(3-pyrrolidin-1-ylpropyl)benzamide582 2.48 124

4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(1H-pyrazol-1-yl)ethyl]benzamide565 1.82 125

4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[3-(1H-imidazol-1-yl)propyl]benzamide579 2.46 126

4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(4-pyrrolidin-1-ylbutyl)benzamide628 2.54 127

4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-[3-(diethylamino)propyl]benzamide616 2.52 128

4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(2-morpholin-4-ylethyl)benzamide616 2.06 129

4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(2-pyrrolidin-1-ylethyl)benzamide600 2.09 130

4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[3-(diethylamino)propyl]benzamide584 2.15 131

4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-morpholin-4-ylethyl)benzamide584 2.13 132

4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(4-pyrrolidin-1-ylbutyl)benzamide596 2.65 133

4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-pyrrolidin-1-ylethyl)benzamide568 2.62 134

4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(dimethylamino)ethyl]benzamide542 2.59 135

4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-methyl-N-[2-(methylsulfonyl)ethyl]benzamide591 2.92 136

3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-pyrrolidin-1-ylethyl)benzamide568 2.11 137

3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[3-(diethylamino)propyl]benzamide584 2.12 138

3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-methoxyethyl)benzamide530 2.60 139

3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(tetrahydrofuran-2-ylmethyl)benzamide582 2.12 140

3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}benzamide630 2.73 141

N-[2-(acetylamino)ethyl]-3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzamide556 2.35 142

3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[3-(1H-imidazol-1-yl)propyl]benzamide579 2.15 143

3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(2-hydroxyethoxy)ethyl]benzamide559 2.38 144

3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(1-methylpyrrolidin-2-yl)ethyl]benzamide582 2.13 145

3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(3-hydroxy-2,2-dimethylpropyl)benzamide557 2.45 146

tert-butyl4-{[(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzoyl)amino]methyl}piperidine-1-carboxylate668 2.79 147

3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(piperidin-4-ylmethyl)benzamide568 2.44 148

3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(3-hydroxypropyl)benzamide529 2.26 149

3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(3-hydroxypropyl)benzamide561 2.32 150

3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(2-hydroxyethyl)benzamide547 2.72 151

3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-hydroxyethyl)benzamide515 2.66 152

N-[2-(acetylamino)ethyl]-3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzamide588 1.82 153

3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-[3-(1H-imidazol-1-yl)propyl]benzamide611 2.59 154

3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(tetrahydrofuran-2-ylmethyl)benzamide587 2.47 155

3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(2-pyridin-4-ylethyl)benzamide608 2.16 156

3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-[3-(diethylamino)propyl]benzamide616 2.18 157

3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]benzamide614 2.16 158

3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(2-pyrrolidin-1-ylethyl)benzamide600 2.17 159

3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(4-pyrrolidin-1-ylbutyl)benzamide628 2.22 160

3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(3-hydroxy-2,2-dimethylpropyl)benzamide589 2.76 161

tert-butyl4-({[3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzoyl]amino}methyl)piperidine-1-carboxylate700 2.86 162

3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(piperidin-4-ylmethyl)benzamide600 2.08 163

4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(tetrahydrofuran-2-ylmethyl)benzenesulfonamide591 2.91 164

4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-morpholin-4-ylethyl)benzenesulfonamide620 2.15 165

4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(2-morpholin-4-ylethyl)benzenesulfonamide652 2.21 166

4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]benzenesulfonamide650 2.22 167

4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(1-methylpyrrolidin-2-yl)ethyl]benzenesulfonamide618 2.16 168

4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-2-methyl-N-(2-morpholin-4-ylethyl)benzenesulfonamide634 2.21 169

4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(tetrahydrofuran-2-ylmethyl)-2-(trifluoromethoxy)benzenesulfonamide675 3.11 170

4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(tetrahydrofuran-2-ylmethyl)-2-(trifluoromethoxy)benzenesulfonamide707 3.18 171

4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-2-methyl-N-(tetrahydrofuran-2-ylmethyl)benzenesulfonamide605 2.59 172

4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-2-methyl-N-(tetrahydrofuran-2-ylmethyl)benzenesulfonamide637 2.69 173

4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(tetrahydrofuran-2-ylmethyl)benzenesulfonamide623 2.66 174

3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-methoxyethyl)benzenesulfonamide565 2.41 175

3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(2-methoxyethyl)benzenesulfonamide597 2.48 176

3-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-methoxyethyl)benzenesulfonamide565 2.63 177

3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(dimethylamino)ethyl]benzenesulfonamide600(M +Na) 2.11 178

3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-[2-(dimethylamino)ethyl]benzenesulfonamide610 2.20 179

N-{1-[4-(aminomethyl)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]urea457 2.55 180

N-(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)-2-methoxyacetamide529 2.52 181

N-{1-[4-(aminomethyl)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea489 2.06 182

N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzyl]-2-methoxyacetamide561 2.38 183

N-[3-tert-butyl-1-(4-{[(2-methoxyethyl)amino]methyl}phenyl)-1H-pyrazol-5-yl]-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea547 2.14 184

N-[1-(4-{[bis(2-hydroxyethyl)amino]methyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-N′-[4-(pyridin-3-yloxy)phenyl]urea545 2.56 185

N-[1-(4-{[bis(2-hydroxyethyl)amino]methyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea577 2.44 186

N-[1-(4-{[bis(3-hydroxypropyl)amino]methyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea573 2.04 187

N-[1-(4-{[bis(3-hydroxypropyl)amino]methyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-N′-[4-(pyridin-3-yloxy)phenyl]urea573 2.21 188

N-[1-(4-{[bis(3-hydroxypropyl)amino]methyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-N′-(2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea605 2.09 189

N2-acetyl-N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)glycinamide556 2.62 190

tert-butyl{2-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)amino]-2-oxoethyl}carbamate614 2.89 191

tert-butyl{2-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)amino]-1-methyl-2-oxoethyl}carbamate628 2.62 192

N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)-2-(1-methyl-1H-imidazol-4-yl)acetamide579 2.45 193

N-(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)glycinamide514 2.21 194

N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzyl]acetamide531 2.79 195

N2-acetyl-N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzyl]glycinamide588 2.26 196

tert-butyl(2-{[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzyl]amino}-2-oxoethyl)carbamate646 2.55 197

tert-butyl(2-{[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzyl]amino}-1-methyl-2-oxoethyl)carbamate660 2.58 198

N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzyl]-2-(1-methyl-1H-imidazol-4-yl)acetamide611 2.06 199

N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzyl]-1-methyl-1H-imidazole-4-carboxamide597 2.22 200

N2-acetyl-N-(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)glycinamide556 2.38 201

tert-butyl{2-[(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)amino]-2-oxoethyl}carbamate613 2.74 202

N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzyl]alaninamide560 2.05 203

N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzyl]glycinamide546 2.10 204

N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)alaninamide528 2.02 205

N-[3-tert-butyl-1-(3-{[(2-hydroxyethyl)amino]methyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea501 2.11 206

N-{1-[3-(aminomethyl)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea457 2.00 207

N-{1-[3-(aminomethyl)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea489 2.09 208

N-(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)acetamide499 2.30 209

N-[3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzyl]acetamide531 2.36 210

N2-acetyl-N-(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)glycinamide556 1.61 211

N-(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)-2-methoxyacetamide529 1.82 212

N2-acetyl-N-[3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzyl]glycinamide588 1.68 213

N-[3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzyl]-2-methoxyacetamide561 1.86 214

N-[3-tert-butyl-1-(3-{[(2,3-dihydroxypropyl)amino]methyl}phenyl)-1H-pyrazol-5-yl]-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea563 2.03 215

N-{3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea490 2.36 216

N-(3-tert-butyl-1-{4-[(2-morpholin-4-ylethoxy)methyl]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea603 2.05 217

N-{3-tert-butyl-1-[4-(methoxymethyl)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea504 2.60 218

N-(3-tert-butyl-1-{4-[(2-morpholin-4-ylethoxy)methyl]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea603 2.05 219

N-{3-tert-butyl-1-[4-(methoxymethyl)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea504 2.60 220

N-(3-tert-butyl-1-{4-[(2-methoxyethoxy)methyl]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea548 2.69 221

ethyl[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)phenyl]acetate546 2.73 222

[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)phenyl]aceticacid 518 2.44 223

N-{3-tert-butyl-1-[4-(2-hydroxyethyl)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea504 2.44 224

N-{3-tert-butyl-1-[4-(2-morpholin-4-yl-2-oxoethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea555 2.36 225

N-{3-tert-butyl-1-[4-(2-oxo-2-pyrrolidin-1-ylethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea539 2.46 226

tert-butyl4-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetyl]piperazine-1-carboxylate654 2.72 227

N-(3-tert-butyl-1-{4-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea568 2.10 228

2-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]acetamide599 2.86 229

2-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-N-(2-methoxyethyl)acetamide543 2.75 230

2-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-N-(2-morpholin-4-ylethyl)acetamide598 2.12 231

N-[3-tert-butyl-1-(4-{2-[(3R)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea555 2.28 232

N-{3-tert-butyl-1-[4-(2-morpholin-4-ylethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea541 1.65 233

N-{3-tert-butyl-1-[4-(2-pyrrolidin-1-ylethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea525 1.69 234

2-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-N-(2-hydroxyethyl)acetamide529 2.20 235

N-[3-tert-butyl-1-(4-{2-[(2-hydroxyethyl)amino]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea515 2.02 236

N-{3-tert-butyl-1-[4-(2-oxo-2-piperazin-1-ylethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea554 2.02 237

N-[3-tert-butyl-1-(4-{2-[(3R)-3-hydroxypyrrolidin-1-yl]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea541 2.04 238

N-{3-tert-butyl-1-[4-(2-piperazin-1-ylethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea540 1.92 239

2-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-N-(2,3-dihydroxypropyl)acetamide559 2.18 240

N-[3-tert-butyl-1-(4-{2-[(2,3-dihydroxypropyl)amino]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea545 2.01 241

N-[3-tert-butyl-1-(4-{2-[(2-methoxyethyl)amino]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea529 2.06 242

N-(3-tert-butyl-1-{4-[2-(4-methylpiperazin-1-yl)ethyl]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea554 2.00 243

N-[3-tert-butyl-1-(4-{2-[(2-morpholin-4-ylethyl)amino]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea584 1.97

1. A compound of Formula I, or a salt, stereoisomer, metabolite orprodrug thereof,

wherein R¹ and R² are independently: (a) hydrogen; (b) (C₁-C₅)alkyl,optionally substituted with one or more of hydroxy or fluoro; or (c)halogen; A is phenyl, pyridine, or pyrimidine, optionally substitutedwith 1 or 2 substituents that are independently (C₁-C₅)alkyl,(C₁-C₅)alkoxy, (C₁-C₅)haloalkyl, (C₁-C₅)haloalkoxy, or halogen; B isphenylene or naphthylene, optionally substituted with 1 to 4substituents that are independently (C₁-C₅)alkyl, (C₁-C₅)alkoxy,(C₁-C₅)haloalkyl, (C₁-C₅)haloalkoxy, or halogen; L is a bridging groupwhich is —O—, —S—, or —CH₂—. M is phenyl, pyridine or pyrimidine,optionally substituted with 1 to 3 substituents that are independently:(1) (C₁-C₅)alkyl; (2) (C₁-C₅)haloalkyl; (3) —O—R³; (4) —NR³R⁴; (5)halogen; (6) —C(O)NR³R⁴; (7) cyano; (8) C(O)R³; (9) —C≡C—R³ or (10)nitro; n is zero or one and X is: (1) —O—; (2) —SO₂—; (3) —NR⁵—; (4)—NR⁵—SO₂—; (5) —N(SO₂NR⁷R⁸)—; (6) —SO₂—NR⁵—; (7) —NR⁵—C(O)—; (8)—C(O)—NR⁵—; (9) —C(O)— or (10) a single bond; Y is a linear or branchedC₁ to C₆ alkyl fragment that is substituted with one or two Z groups,where each Z group is independently: (1) —OR⁶; (2) —O—C(O)—R⁶; (3)—NR⁷R⁸; (4) —SO₂—(C₁-C₅)alkyl; (5) —C(O)—O—R⁶; (6) —NH—C(O)—R⁶; (7)—C(O)—NR⁷R⁸ or (8) a monocyclic, saturated, partially saturated, oraromatic heterocycle of 5-7 ring atoms containing at least oneheteroatom selected from N, O, or S, that is optionally substituted with1 to 3 substituents selected from (C₁-C₅)alkyl, (C₁-C₅)haloalkyl,hydroxy, amino, halogen, or oxo; with the proviso that when n is zeroand X is —O—, —NR³—, or a single bond, then Z is not morpholine,piperidine, imidazole, or tetrazole; with the further proviso that whenn is zero and X is a single bond, then Z is not —NR⁷R⁸; R³, R⁴, R⁵ andR⁶ are each independently hydrogen or (C₁-C₅)alkyl optionallysubstituted with hydroxy; and R⁷ and R⁸ are independently hydrogen, or(C₁-C₅)alkyl optionally substituted with hydroxy; or the group —NR⁷R⁸forms a monocyclic saturated heterocyclic ring having 5 to 7 ring atomsoptionally substituted on a carbon atom with hydroxy, where, in additionto the nitrogen atom in the group —NR⁷R⁸, zero to two of the other ringatoms is a hetero atom selected from N, O and S, and the remaining ringatoms are carbon.
 2. A compound as in claim 1 wherein R¹ is (C₁-C₅)alkyland R² is hydrogen.
 3. A compound as in claim 1 wherein R¹ istert-butyl, isopropyl, or cyclopentyl and R² is hydrogen.
 4. A compoundas in claim 1 wherein A is phenyl or pyridine optionally substitutedwith 1 or 2 substituents which are independently (C₁-C₅)alkyl,(C₁-C₅)alkoxy or halogen.
 5. A compound as in claim 1 wherein A is astructure of formulae 1x or 1xx:

wherein R^(a) is methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,bromine, chlorine or fluorine and n, X and Y are as defined in claim 1and the pyrazole ring and the group, —(CH₂)_(n)—X—Y are not bound tocontiguous ring carbons of A, but rather have 1 or 2 ring carbonsseparating them.
 6. A compound as in claim 1 wherein B is phenylene,optionally substituted with 1 to 2 halogen atoms and is of the formula2×:

wherein R^(b) is fluorine or chlorine and the urea group and thebridging group are not bound to contiguous ring carbons of B, but ratherhave 1 or 2 ring carbons separating them.
 7. A compound as in claim 1wherein B is of one of the following formulae:


8. A compound as in claim 1 wherein M is of one of the followingformulas:

wherein R^(c) is: (1) (C₁-C₅)alkyl; (2) (C₁-C₅)haloalkyl; (3) —O—R³; (4)—NR³R⁴; (5) halogen; (6) —C(O)NR³R⁴; (7) cyano; (8) C(O)R; (9) —C≡C—R³or (10) nitro.
 9. A compound of claim 1 wherein X is —O—; —NR⁵—;—NR⁵—C(O)—; —C(O)—NR⁵— or a single bond.
 10. A compound of claim 1wherein Y is a linear or branched C₁ to C₄ alkyl fragment that issubstituted with one Z group selected from —OR⁶; —NR⁷R⁸; —NH—C(O)—R⁶ or—C(O)—NR⁷R⁸.
 11. A compound of claim 1 wherein Y is methylene, ethylene,n-propylene, or n-butylene.
 12. A compound as in claim 1 wherein R³, R⁴,R⁵ and R⁶ are each independently hydrogen, methyl, ethyl, propyl orbutyl, optionally substituted with hydroxy.
 13. A compound as in claim1, wherein Z is —NR⁷R⁸, which is in the form of a monocyclic saturatedheterocyclic ring group selected from pyrrolidine, piperidine, azepane,morpholine, thiomorpholine, piperazine, and homopiperazine, eachoptionally substituted on a carbon atom with hydroxy.
 14. A compound ofclaim 1 wherein, R⁷ and R⁸ are each independently hydrogen, methyl,ethyl, propyl or butyl, optionally substituted with hydroxy.
 15. Acompound of Formula II, or a salt, stereoisomer, metabolite or prodrugthereof,

wherein R^(b) is fluorine or chlorine; R¹ and R² are independently: (a)hydrogen; (b) (C₁-C₅)alkyl, optionally substituted with one or morehydroxy or fluoro; or (c) halogen. R^(c) is: (C₁-C₅)alkyl;(C₁-C₅)haloalkyl; —O—R³; —NR³R⁴; halogen; —C(O)NR³R⁴; cyano; C(O)R³;—C≡C—R³ or nitro; A is phenyl, pyridine, or pyrimidine, optionallysubstituted with 1 or 2 substituents that are independently(C₁-C₅)alkyl, (C₁-C₅)alkoxy, (C₁-C₅)haloalkyl, (C₁-C₅)haloalkoxy orhalogen; Y is a linear or branched C₁ to C₆ alkyl fragment that issubstituted with one or two Z groups, where each Z group isindependently: (1) —OR⁶; (2) —O—C(O)—R⁶; (3) —NR⁷R⁸; (4)—SO₂—(C₁-C₅)alkyl; (5) —C(O)—O—R⁶; (6) —NH—C(O)—R⁶; (7) —C(O)—NR⁷R⁸; or(8) a monocyclic, saturated, partially saturated, or aromaticheterocycle of 5-7 ring atoms containing at least one heteroatomselected from N, O, or S, that is optionally substituted with 1 to 3substituents selected from (C₁-C₅)alkyl, (C₁-C₅)haloalkyl, hydroxy,amino, halogen, or oxo; with the proviso that when n is zero and X is—O—, —NR³—, or a single bond, then Z is not morpholine, piperidine,imidazole, or tetrazole; with the further proviso that when n is zeroand X is a single bond, then Z is not —NR⁷R⁸; R³, R⁴, R⁵ and R⁶ are eachindependently hydrogen or (C₁-C₅)alkyl optionally substituted withhydroxy; R⁷ and R⁸ are independently hydrogen, or (C₁-C₅)alkyloptionally substituted with hydroxy; or the group —NR⁷R⁸ forms amonocyclic saturated heterocyclic ring having 5 to 7 ring atoms,optionally substituted on a carbon atom with hydroxy where, in additionto the nitrogen atom attached to the rest of the molecule, zero to twoof the other ring atoms is a hetero atom selected from N, O and S, andthe remaining ring atoms are carbon.
 16. A compound as in claim 15wherein R¹ is (C₁-C₅)alkyl and R² is hydrogen.
 17. A compound as inclaim 15 wherein R¹ is tert-butyl, isopropyl, or cyclopentyl and R² ishydrogen.
 18. A compound as in claim 15 wherein A is phenyl or pyridineoptionally substituted with 1 or 2 substituents which are independently(C₁-C₅)alkyl, (C₁-C₅)alkoxy or halogen.
 19. A compound as in claim 15wherein A is a structure of formulae 1x or 1xx:

wherein R^(a) is methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,bromine, chlorine or fluorine and n is zero or one and X is: (1) —O—;(3) —NR⁵—; (4) —NR⁵—SO₂—; (5) —N(SO₂NR⁷R⁸)—; (6) —SO₂—NR²—; (7)—NR⁵—C(O)—; (8) —C(O)—NR⁵—; (9) —C(O)— or (10) a single bond; Y is alinear or branched C₁ to C₆ alkyl fragment that is substituted with oneor two Z groups, where each Z group is independently: (1) —OR⁶; (2)—O—C(O)—R⁶; (3) —NR⁷R⁸; (4) —SO₂—(C₁-C₅ alkyl; (5) —C(O)—O—R⁶; (6)—NH—C(O)—R⁶; (7) —C(O)—NR⁷R⁸ or (8) a monocyclic saturated, partiallysaturated, or aromatic heterocycle of 5-7 ring atoms containing at leastone heteroatom selected from N, O or S, that is optionally substitutedwith 1 to 3 substituents selected from (C₁-C₅)alkyl, (C₁-C₅)haloalkyl,hydroxy, amino, halogen, or oxo; with the proviso that when n is zeroand X is —O—, —NR³—, or a single bond, then Z is not morpholine,piperidine, imidazole, or tetrazole; with the further proviso that whenn is zero and X is a single bond, then Z is not —NR⁷R⁸; and the pyrazolering and the group, —(CH₂)_(n)—X—Y, are not bound to contiguous ringcarbons of A.
 20. A compound of claim 15 wherein Y is a linear orbranched C₁ to C₄ alkyl fragment that is substituted with one Z groupselected from —OR⁶; —NR⁷R⁸; —NH—C(O)—R⁶ or —C(O)—NR⁷R⁸.
 21. A compoundof claim 15 wherein Y is methylene, ethylene, n-propylene, orn-butylene.
 22. A compound as in claim 15 wherein R³, R⁴, R⁵ and R⁶ areeach independently hydrogen, methyl, ethyl, propyl or butyl, optionallysubstituted with hydroxy.
 23. A compound as in claim 15, wherein Z is—NR⁷R⁸, which is in the form of a monocyclic saturated heterocyclic ringgroup selected from pyrrolidine, piperidine, azepane, morpholine,thiomorpholine, piperazine, and homopiperazine, each optionallysubstituted on a carbon atom with hydroxy.
 24. A compound of claim 15wherein, R⁷ and R⁸ are each independently selected from hydrogen,methyl, ethyl, propyl or butyl, optionally substituted with hydroxy. 25.A compound of Formulae III or IV, or a salt, stereoisomer, metabolite orprodrug thereof:

wherein R^(a) is methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,bromine, chlorine or fluorine; R^(c) is selected from (C₁-C₅)alkyl;(C₁-C₅)haloalkyl; —O—R³; —NR³R⁴; halogen; —C(O)NR³R⁴; cyano; C(O)R³;—C≡C—R³; or nitro; and R^(z) is tert-butyl, isopropyl, or cyclopentyl; nis zero or one and X is: —O—; —SO₂—; —NR⁵—; —NR⁵—SO₂—; —N(SO₂NR⁷R⁸)—;—SO₂—NR⁵—; —NR⁵—C(O)—; —C(O)—NR⁵—; —C(O)—; or a single bond; Y is alinear or branched C₁ to C₆ alkyl fragment that is substituted with oneor two Z groups, where each Z group is independently selected from: (1)—OR⁶; (2) —O—C(O)—R⁶; (3) —NR⁷R⁸; (4) —SO₂—(C₁-C₅)alkyl; (5) —C(O)—O—R⁶;(6) —NH—C(O)—R⁶; (7) —C(O)—NR⁷R⁸; or (8) a monocyclic, saturated,partially saturated, or aromatic heterocycle of 5-7 ring atomscontaining at least one heteroatom which is N, O, or S, that isoptionally substituted with 1 to 3 substituents selected from(C₁-C₅)alkyl, (C₁-C₅)haloalkyl, hydroxy, amino, halogen, or oxo; withthe proviso that when n is zero and X is —O—, —NR³—, or a single bond,then Z is not morpholine, piperidine, imidazole, or tetrazole; with thefurther proviso that when n is zero and X is a single bond, then Z isnot —NR⁷R⁸; R³, R⁴, R⁵ and R⁶ are each independently hydrogen or(C₁-C₅)alkyl optionally substituted with hydroxy; R⁷ and R⁸ areindependently hydrogen, or (C₁-C₅)alkyl optionally substituted withhydroxy; or the group —NR⁷R⁸ forms a monocyclic saturated heterocyclicring having 5 to 7 ring atoms, where, in addition to the nitrogen atomattached to the group —NR⁷R⁸, zero to two of the other ring atoms is ahetero atom selected from N, O and S, and the remaining ring atoms arecarbon.
 26. A compound of claim 25 wherein Y is a linear or branched C₁to C₄ alkyl fragment that is substituted with one Z group which is —OR⁶;—NR⁷R⁸; —NH—C(O)—R⁶ or —C(O)—NR⁷R⁸.
 27. A compound of claim 25 wherein Yis methylene, ethylene, n-propylene or n-butylene.
 28. A compound as inclaim 25 wherein R³, R⁴, R⁵ and R⁶ are each independently hydrogen,methyl, ethyl, propyl or butyl, optionally substituted with hydroxy. 29.A compound as in claim 25, wherein Z is —NR⁷R⁸, which is in the form ofa monocyclic saturated heterocyclic ring group selected frompyrrolidine, piperidine, azepane, morpholine, thiomorpholine,piperazine, and homopiperazine, each optionally substituted on a carbonatom with hydroxy.
 30. A compound of claim 25 wherein, R⁷ and R⁸ areeach independently hydrogen or methyl, ethyl, propyl or butyl,optionally substituted with hydroxy.
 31. A compound of Formula V and VI,or a salt, stereoisomer, metabolite or prodrug thereof:

wherein Hal is bromine, chlorine or fluorine; n is zero or one; X is:—O—; —NR⁵—; —NR⁵—C(O)—; —C(O)—NR⁵— or a single bond; and Y is:methylene, ethylene, n-propylene or n-butylene substituted with one Zgroup which is: —OR⁶; —NR⁷R⁸; —NH—C(O)—R⁶ or —C(O)—NR⁷R⁸ with theproviso that when n is zero and X is a single bond, then Z is not —NR⁷R⁸R⁵ and R⁶ are each independently selected from hydrogen, methyl, ethyl,propyl or butyl, optionally substituted with hydroxy and R⁷ and R⁸ areeach independently selected from hydrogen, methyl, ethyl, propyl orbutyl, optionally substituted with hydroxy.
 32. The following compounds:4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-pyrrolidin-1-ylethyl)benzamideN-{3-tert-butyl-1-[4-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-(3-tert-butyl-1-{4-[2-(diethylamino)ethoxy]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(2-piperidin-4-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]ureaN-{3-tert-butyl-1-[3-(3-hydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl3-methoxypropanamideN-(3-tert-butyl-1-{4-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea4-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-2,2-dimethyl-4-oxobutanoicacidN-(3-tert-butyl-1-{4-[(4-hydroxy-3,3-dimethylbutyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-(3-tert-butyl-1-{3-[(3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-(3-tert-butyl-1-{3-[[(dimethylamino)sulfonyl](3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-(1-{3-[bis(2-hydroxyethyl)amino]phenyl}-3-tert-butyl-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{1-[4-(aminomethyl)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)-phenyl]ureaN-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)-2-methoxyacetamideN-[3-tert-butyl-1-(4-{[(2-methoxyethyl)amino]methyl}phenyl}-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-[1-(4-{[bis(2-hydroxyethyl)amino]methyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)glycinamide3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]benzamide3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]benzamide3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(2,3-dihydroxypropyl)benzamide3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2,3-dihydroxypropyl)benzamideN-{3-tert-butyl-1-[4-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-(3-tert-butyl-1-{4-[(2-methoxyethoxy)methyl]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-2-methyl-N-(2-morpholin-4-ylethyl)benzenesulfonamideethyl(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetate(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)aceticacidN-{3-tert-butyl-1-[4-(2-hydroxyethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-[3-tert-butyl-1-(4-{2-[(3S)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-[3-tert-butyl-1-(4-{2-[(3S)-3-hydroxypyrrolidin-1-yl]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]ureamethylN-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetyl]-L-serinateN-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetyl]-L-serineN-{3-tert-butyl-1-[4-(2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}ethyl)phenyl}-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(2-piperidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(2-morpholin-4-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(3-morpholin-4-ylpropoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-{3-tert-butyl-1-[4-(3-morpholin-4-ylpropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(3-morpholin-4-ylpropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-{3-tert-butyl-1-[4-(3-hydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-{3-tert-butyl-1-[4-(3-hydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(3-hydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-{3-tert-butyl-1-[4-(2-piperidin-4-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureabutyl4-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenoxy)butanoatebutyl4-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)phenoxy]butanoateN-{1-[4-(2-aminoethoxy)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}urea4-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)phenoxy]butanoicacid4-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenoxy)butanoicacidN-{3-tert-butyl-1-[4-(2-piperidin-4-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{1-[4-(2-aminoethoxy)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{1-[4-(2-aminoethoxy)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy]-phenyl]ureaN-{3-tert-butyl-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-{3-tert-butyl-1-[4-(2-hydroxyethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(2,3-dihydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(2,3-dihydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-{3-tert-butyl-1-[3-(3-morpholin-4-ylpropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{3-tert-butyl-1-[3-(3-morpholin-4-ylpropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]ureaN-{3-tert-butyl-1-[3-(3-morpholin-4-ylpropoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-{3-tert-butyl-1-[3-(3-hydroxypropoxy)phenyl]H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-{3-tert-butyl-1-[3-(3-hydroxypropoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]ureaN-{3-tert-butyl-1-[3-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-{3-tert-butyl-1-[3-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)phenyl]ureaN-{3-tert-butyl-1-[3-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)phenyl]-3-methoxypropanamideN-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino}-1H-pyrazol-1-yl}phenyl]2-methoxyacetamideN-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)phenyl]-2-methoxyacetamide2-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-2-oxoethylacetate2-bromo-N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)acetamideN-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-morpholin-4-ylacetamideN-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-pyrrolidin-1-ylacetamideN-(3-tert-butyl-1-{4-[(2-morpholin-4-ylethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-methoxyacetamideN-(3-tert-butyl-1-{4-[(2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-(3-tert-butyl-1-{4-[(2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-3-yloxy)phenyl]ureaN-(3-tert-butyl-1-{4-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-3-yloxy)phenyl]ureaN-(3-tert-butyl-1-{4-[(3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-(3-tert-butyl-1-{4-[(3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-3-yloxy)phenyl]urea4-[(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-4-oxobutanoicacid4-[(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-4-oxobutanoicacid4-[(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-2,2-dimethyl-4-oxobutanoicacidN-(3-tert-butyl-1-{4-[(2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-(3-tert-butyl-1-{4-[(3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-(3-tert-butyl-1-{4-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-(3-tert-butyl-1-{4-[[(dimethylamino)sulfonyl](2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-methoxyacetamideN-(3-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-methoxyacetamideN-(3-tert-butyl-1-{3-[(2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-(3-tert-butyl-1-{3-[(2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-3-yloxy)phenyl]ureaN-(3-tert-butyl-1-{3-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-(3-tert-butyl-1-{3-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-3-yloxy)phenyl]ureaN-(3-tert-butyl-1-{3-[(3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-3-yloxy)phenyl]urea4-[(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-4-oxobutanoicacid4-[(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-2,2-dimethyl-4-oxobutanoicacid4-[(3-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-4-oxobutanoicacid4-[(3-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)amino]-2,2-dimethyl-4-oxobutanoicacidN-[3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)phenyl]-2-methoxyacetamideN-(3-tert-butyl-1-{3-[(2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-(3-tert-butyl-1-{3-[(3-hydroxypropyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-(3-tert-butyl-1-{3-[(2-methoxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-morpholin-4-ylacetamideN-(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-2-(1H-imidazol-1-yl)acetamideN-(3-tert-butyl-1-{3-[[(dimethylamino)sulfonyl](2-hydroxyethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-(3-tert-butyl-1-{3-[(2-morpholin-4-ylethyl)amino]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-methoxyethyl)benzamide4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-methoxyethyl)-N-methylbenzamide4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-methyl-N-[2-(methylsulfonyl)ethyl]benzamide4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(4-pyrrolidin-1-ylbutyl)benzamide4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-morpholin-4-ylethyl)benzamide4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[3-(diethylamino)propyl]benzamide4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(dimethylamino)ethyl]benzamide4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(3-pyrrolidin-1-ylpropyl)benzamide4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(1H-pyrazol-1-yl)ethyl]benzamide4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-2-(1H-imidazol-1-yl)propyl]benzamide4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(4-pyrrolidin-1-ylbutyl)benzamide4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-[3-(diethylamino)propyl]benzamide4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(2-morpholin-4-ylethyl)benzamide4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(2-pyrrolidin-1-ylethyl)benzamide4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[3-(diethylamino)propyl]benzamide4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-morpholin-4-ylethyl)benzamide4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(4-pyrrolidin-1-ylbutyl)benzamide4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-pyrrolidin-1-ylethyl)benzamide4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(dimethylamino)ethyl]benzamide4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-methyl-N-[2-(methylsulfonyl)ethyl]benzamide3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-pyrrolidin-1-ylethyl)benzamide3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[3-(diethylamino)propyl]benzamide3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-methoxyethyl)benzamide3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(tetrahydrofuran-2-ylmethyl)benzamide3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}benzamideN-[2-(acetylamino)ethyl]-3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}-carbonyl)amino]-1H-pyrazol-1-yl}benzamide3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[3-(1H-imidazol-1-yl)propyl]benzamide3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(2-hydroxyethoxy)ethyl]benzamide3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(1-methylpyrrolidin-2-yl)ethyl]benzamide3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(3-hydroxy-2,2-dimethylpropyl)benzamidetert-butyl4-{[(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzoyl)amino]methyl}piperidine-1-carboxylate3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(piperidin-4-ylmethyl)benzamide3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(3-hydroxypropyl)benzamide3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(3-hydroxypropyl)benzamide3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(2-hydroxyethyl)benzamide3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-hydroxyethyl)benzamideN-[2-(acetylamino)ethyl]-3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)benzamide3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-[3-(1H-imidazol-1-yl)propyl]benzamide3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(tetrahydrofuran-2-ylmethyl)benzamide3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(2-pyridin-4-ylethyl)benzamide3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-[3-(diethylamino)propyl]benzamide3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]benzamide3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(2-pyrrolidin-1-ylethyl)benzamide3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(4-pyrrolidin-1-ylbutyl)benzamide3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(3-hydroxy-2,2-dimethylpropyl)benzamide3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(piperidin-4-ylmethyl)benzamide4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(tetrahydrofuran-2-ylmethyl)benzenesulfonamide4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-morpholin-4-ylethyl)benzenesulfonamide4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(2-morpholin-4-ylethyl)benzenesulfonamide4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]benzenesulfonamide4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(1-methylpyrrolidin-2-yl)ethyl]benzenesulfonamide4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-2-methyl-N-(2-morpholin-4-ylethyl)benzenesulfonamide4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(tetrahydrofuran-2-ylmethyl}2-(trifluoromethoxy)benzenesulfonamide4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(tetrahydrofuran-2-ylmethyl)-2-(trifluoromethoxy)benzenesulfonamide4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-2-methyl-N-(tetrahydrofuran-2-ylmethyl)benzenesulfonamide4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-2-methyl-N-(tetrahydrofuran-2-ylmethyl)benzenesulfonamide4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(tetrahydrofuran-2-ylmethyl)benzenesulfonamide3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-methoxyethyl)benzenesulfonamide3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-(2-methoxyethyl)benzenesulfonamide3-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-(2-methoxyethyl)benzenesulfonamide3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}-N-[2-(dimethylamino)ethyl]benzenesulfonamide3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)-N-[2-(dimethylamino)ethyl]benzenesulfonamideN-{1-[4-(aminomethyl)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-[4-(pyridin-3-yloxy)-phenyl]ureaN-(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)-2-methoxyacetamideN-{1-[4-(aminomethyl)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)benzyl]-2-methoxyacetamideN-[3-tert-butyl-1-(4-{[(2-methoxyethyl)amino]methyl}phenyl)-1H-pyrazol-5-yl]-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-[1-(4-{[bis(2-hydroxyethyl)amino]methyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-N′-[4-(pyridin-3-yloxy)phenyl]ureaN-[1-(4-{[bis(2-hydroxyethyl)amino]methyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-[1-(4-{[bis(3-hydroxypropyl)amino]methyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-[1-(4-{[bis(3-hydroxypropyl)amino]methyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-N′-[4-(pyridin-3-yloxy)phenyl]ureaN-[1-(4-{[bis(3-hydroxypropyl)amino]methyl}phenyl)-3-tert-butyl-1H-pyrazol-5-yl]-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN2-acetyl-N-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)glycinamideN-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl2-(1-methyl-1H-imidazol-4-yl)acetamideN-(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)glycinamideN-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)benzyl]acetamideN2-acetyl-N-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}-amino)carbonyl]amino}-1H-pyrazol-1-yl)benzyl]glycinamideN-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)benzyl]-2-(1-methyl-1H-imidazol-4-yl)acetamideN-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)-carbonyl]amino}-1H-pyrazol-1-yl)benzyl]-1-methyl-1H-imidazole-4-carboxamideN2-acetyl-N-(4-{3-tert-butyl-5-[({[4-(pyridin-3-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)glycinamideN-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)benzyl]alaninamideN-[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)benzyl]glycinamideN-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)alaninamideN-[3-tert-butyl-1-(3-{[(2-hydroxyethyl)amino]methyl}phenyl}-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{1-[3-(aminomethyl)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{1-[3-(aminomethyl)phenyl]-3-tert-butyl-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)acetamideN-[3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)benzyl]acetamideN2-acetyl-N-(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)glycinamideN-(3-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}benzyl)-2-methoxyacetamideN2-acetyl-N-[3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}-amino)carbonyl]amino}-1H-pyrazol-1-yl)benzyl]glycinamideN-[3-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)benzyl]-2-methoxyacetamideN-[3-tert-butyl-1-(3-{[(2,3-dihydroxypropyl)amino]methyl}phenyl)-1H-pyrazol-5-yl]-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-{3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-(3-tert-butyl-1-{4-[(2-morpholin-4-ylethoxy)methyl]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-{3-tert-butyl-1-[4-(methoxymethyl)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-(3-tert-butyl-1-{4-[(2-morpholin-4-ylethoxy)methyl]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-{3-tert-butyl-1-[4-(methoxymethyl)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-(3-tert-butyl-1-{4-[(2-methoxyethoxy)methyl]phenyl}-1H-pyrazol-5-yl)-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaethyl[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]-amino}-1H-pyrazol-1-yl)phenyl]acetate[4-(3-tert-butyl-5-{[({2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}amino)carbonyl]amino}-1H-pyrazol-1-yl)phenyl]aceticacidN-{3-tert-butyl-1-[4-(2-hydroxyethyl)phenyl]-1H-pyrazol-5-yl}-N′-{2-fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}ureaN-{3-tert-butyl-1-[4-(2-morpholin-4-yl-2-oxoethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(2-oxo-2-pyrrolidin-1-ylethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-(3-tert-butyl-1-{4-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]urea2-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]acetamide2-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-N-(2-methoxyethyl)acetamide2-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-N-(2-morpholin-4-ylethyl)acetamideN-[3-tert-butyl-1-(4-{2-[(3R)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(2-morpholin-4-ylethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(2-pyrrolidin-1-ylethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea2-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-N-(2-hydroxyethyl)acetamideN-[3-tert-butyl-1-(4-{2-[(2-hydroxyethyl)amino]ethyl}phenyl1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(2-oxo-2-piperazin-1-ylethyl)phenyl]-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-[3-tert-butyl-1-(4-{2-[(3R)-3-hydroxypyrrolidin-1-yl]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-{3-tert-butyl-1-[4-(2-piperazin-1-ylethyl)phenyl]-1H-pyrazol-5-yl}-N′-[4-(pyridin-4-yloxy)phenyl]urea2-(4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)amino]-1H-pyrazol-1-yl}phenyl)-N-(2,3-dihydroxypropyl)acetamideN-[3-tert-butyl-1-(4-{2-[(2,3-dihydroxypropyl)amino]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-[3-tert-butyl-1-(4-{2-[(2-methoxyethyl)amino]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-(3-tert-butyl-1′-{4-[2-(4-methylpiperazin-1-yl)ethyl]phenyl}-1H-pyrazol-5-yl)-N′-[4-(pyridin-4-yloxy)phenyl]ureaN-[3-tert-butyl-1′-(4-{2-[(2-morpholin-4-ylethyl)amino]ethyl}phenyl)-1H-pyrazol-5-yl]-N′-[4-(pyridin-4-yloxy)phenyl]urea.33. A pharmaceutical composition comprising a compound of claim 1 or apharmaceutically acceptable salt, prodrug, stereoisomer or metabolitethereof, and a physiologically acceptable carrier.
 34. A method oftreating hyper-proliferative disorders comprising administering to amammal in need thereof a therapeutically effective amount of a compoundof claim 1 or a pharmaceutically acceptable salt or ester thereof.
 35. Amethod according to claim 34, wherein said hyper-proliferative disorderis cancer.
 36. A method according to claim 34 or 35, wherein said canceris of the breast, respiratory tract, brain, reproductive organs,digestive tract, urinary tract, eye, liver, skin, head and/or neck,thyroid, parathyroid and/or their distant metastases.
 37. A methodaccording to claim 34 or 35, wherein said cancer is lymphoma, sarcoma,or leukemia.
 38. A method according to claim 36, wherein said breastcancer is invasive ductal carcinoma, invasive lobular carcinoma, ductalcarcinoma in situ, or lobular carcinoma in situ.
 39. A method accordingto claim 36, wherein said respiratory tract cancer is small-cell lungcarcinoma, non-small-cell lung carcinoma, bronchial adenoma orpleuropulmonary blastoma.
 40. A method according to claim 36, whereinsaid brain cancer is a tumor of the brain stem, hypothalamic glioma,cerebellar astrocytoma, cerebral astrocytoma, medulloblastoma,ependymoma, neuroectodermal or pineal tumor.
 41. A method according toclaim 36, wherein said tumor of the male reproductive organ is aprostate or testicular cancer.
 42. A method according to claim 36,wherein said cancer of the female reproductive organ is endometrial,cervical, ovarian, vaginal, vulvar, or sarcoma of the uterus.
 43. Amethod according to claim 36, wherein said cancer of the digestive tractis anal, colon, colorectal, esophageal, gallbladder, gastric,pancreatic, rectal, small-intestine or salivary gland.
 44. A methodaccording to claim 36, wherein said cancer of the urinary tract isbladder, penile, kidney, renal pelvis, ureter or urethral.
 45. A methodaccording to claim 36, wherein said eye cancer is intraocular melanomaor retinoblastoma.
 46. A method according to claim 36, wherein saidliver cancer is hepatocellular carcinoma, liver cell carcinomas with orwithout fibrolamellar variant, cholangiocarcinoma or mixedhepatocellular cholangiocarcinoma.
 47. A method according to claim 36,wherein said skin cancer is squamous cell carcinoma, Kaposi's sarcoma,malignant melanoma, Merkel cell skin cancer or non-melanoma skin cancer.48. A method according to claim 36, wherein said head-and-neck cancer islaryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal, lip or oralcavity cancer.
 49. A method according to claim 36, wherein said lymphomais AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-celllymphoma, Hodgkin's disease or lymphoma of the central nervous system.50. A method according to claim 36, wherein said sarcomas is a sarcomaof the soft tissue, osteosarcoma, malignant fibrous histiocytoma,lymphosarcoma or rhabdomyosarcoma.
 51. A method according to claim 36,wherein said leukemia is acute myeloid leukemia, acute lymphoblasticleukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia orhairy cell leukemia.
 52. A method of treating angiogenesis disorderscomprising administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt or ester thereof.
 53. A composition of claim 33, furtherincluding an additional pharmaceutical agent.
 54. A composition of claim33, further including an additional anti-hyper-proliferative agent. 55.A composition of claim 55, wherein said additionalanti-hyper-proliferative agent is epothilone or its derivative,irinotecan, raloxifen or topotecan.
 56. A composition of claim 54,wherein said additional pharmaceutical agent is aldesleukin, alendronicacid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi,altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine,anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin,5-azacytidine, azathioprine, BCG or tice BCG, bestatin, betamethasoneacetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate,broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine,carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil,cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadronphosphate, delestrogen, denileukin diftitox, depo-medrol, deslorelin,dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine,doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend,epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, estrace,estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyol,etidronic acid, etopophos, etoposide, fadrozole, farston, filgrastim,finasteride, fligrastim, floxuridine, fluconazole, fludarabine,5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU),fluoxymesterone, flutamide, formestane, fosteabine, fotemustine,fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel,goserelin, granisetron HCl, histrelin, hycamtin, hydrocortone,eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan,idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferonalfa-2A, interferon alfa-2B, interferon alfa-n1, interferon alfa-n3,interferon beta, interferon gamma-1a, interleukin-2, intron A, iressa,irinotecan, kytril, lentinan sulphate, letrozole, leucovorin,leuprolide, leuprolide acetate, levamisole, levofolinic acid calciumsalt, levothroid, levoxyl, lomustine, lonidamine, marinol,mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrolacetate, melphalan, menest, 6-mercaptopurine, Mesna, methotrexate,metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone,Modrenal, Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide,nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCl, orapred,oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin,picibanil, pilocarpine HCl, pirarubicin, plicamycin, porfimer sodium,prednimustine, prednisolone, prednisone, premarin, procarbazine,procrit, raltitrexed, rebif, rhenium-186 etidronate, rituximab,roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine,sizofuran, sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy,streptozocin, strontium-89 chloride, synthroid, tamoxifen, tamsulosin,tasonermin, tastolactone, taxotere, teceleukin, temozolomide,teniposide, testosterone propionate, testred, thioguanine, thiotepa,thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab,trastuzumab, treosulfan, tretinoin, trexall, trimethylmelamine,trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine,valrubicin, vesnarinone, vinblastine, vincristine, vindesine,vinorelbine, virulizin, zinecard, zinostatin stimalamer, zofran,ABI-007, acolbifene, actimmune, affinitak, aminopterin, arzoxifene,asoprisnil, atamestane, atrasentan, BAY 43-9006, avastin, CCI-779,CDC-501, celebrex, cetuximab, crisnatol, cyproterone acetate,decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin,eflornithine, exatecan, fenretinide, histamine dihydrochloride,histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid,interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin,L-651582, lanreotide, lasofoxifene, libra, lonafarnib, miproxifene,minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin,neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxelpolyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, R-1549,raloxifene, ranpirnase, 13-cis-retinoic acid, satraplatin, seocalcitol,T-138067, tarceva, taxoprexin, thymosin alpha 1, tiazofurine,tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar,vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acidor combinations thereof.